pH DEPENDENT CARRIERS FOR TARGETED RELEASE OF PHARMACEUTICALS ALONG THE GASTROINTESTINAL TRACT, COMPOSITIONS THEREFROM, AND MAKING AND USING SAME

ABSTRACT

Novel drug carriers capable of targeted and/or pH dependent release of biologically active agents into selected pH environments including the gastrointestinal (GI), ophthalmic, urinary, or reproductive tracts. Unexpectedly, carriers including free fatty acids (FFA) are able to deliver biologically active agents to various pH environments. Such targeted delivery is tailorable and useful for active agents that are: (a) injurious to the upper GI tract (esophagus, stomach, and duodenum), (b) acid labile, (c) impermeable/insoluble compounds in GI fluids, (d) susceptible to first pass metabolism, and/or (e) cause stomach irritation, upset, or dyspepsia.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/631,963, filed on Sep. 29, 2012, which claims priority from U.S.Provisional Patent Application No. 61/540,699, filed on Sep. 29, 2011.The contents of these applications are incorporated herein by referencein their entirety.

BACKGROUND OF THE INVENTION 1. Field of the Invention

Embodiments of the present invention relate to targeted release carriersand/or pH dependent release carriers and compositions including atargeted release and/or pH dependent release carrier of this inventionand at least one biologically active agent and to methods for making andusing same.

More particularly, embodiments of the present invention relate totargeted release carriers and/or pH dependent release carriers andcompositions including a targeted release and/or pH dependent releasecarrier of this invention and an effective amount of at least one activeagent (one active agent or a plurality of active agents), where thetargeted release and/or pH dependent release carriers include at leastone biocompatible agents (one active agent or a plurality ofbiocompatible agents), and where the active agents include nutraceuticalagents and/or pharmaceutical agents and where the targeted releaseand/or pH dependent release carriers include at least one targetedrelease and/or pH dependent release agent for the active agents so thatthe biologically active agents may be released into the tracts of ananimal, mammal, or human in a targeted manner. Embodiments of theinvention also relate to methods for making and using the carriersand/or compositions.

2. Description of the Related Art

U.S. Pat. No. 4,666,701 disclosed gamma-linolenic acid ordihomo-gamma-linolenic acid for use in the reduction or prevention ofgastrointestinal bleeding and other side effects of non-steroidal,anti-inflammatory drugs (NSAIDs), when administered on a continuingbasis, including use in allowing said administration to be replaced byadministration of said acid alone in arthritis and other conditionswithout exacerbation of symptoms. This patent also included no teachingon targeted release of biologically active agents mediated by free fattyacids.

However, free fatty acids are known to be injurious to the upper GItract. See, e.g., Velasquez et al. “Oleic acid-induced mucosal injury indeveloping piglets intestine.” Am. J. Physiol 64, g576-81, 1993;Velasquez et al. “Fatty acid-induced injury in developing pigletintestine: effect of degree of saturation and carbon chain length.”Pediatr. Res. 33, 543-7, 1993; and such membrane injuries action hasbeen therapeutically exploited (See Croffie et al. “Sclerosing agentsfor use in GI endoscopy,” Gastrointestinal Endoscopy 66, 1-6, 2007(ethanolamine oleate, a drug used to induce endothelial membrane damagefor the treatment of esophageal varices). Thus, the formulations of thisinvention include large quantities of two components known to beinjurious to the upper GI tract, an NSAID and free fatty acids(Davenport, “Gastric mucosal injury by fatty and acetylsalicylic acids”,Gastroenterology, 46, 245-253, 1964, yet the formulations of thisinvention show comparable if not superior protection against NSAID GItoxicity.

U.S. patent application Ser. No. 10/433,454 filed 6 Nov. 2003 discloseda composition including a biocompatible oil carrier having a relativelyhigh phospholipid content for non-steroidal anti-inflammatory drugs(NSAIDs) showing reduced gastrointestinal (GI) NSAID toxicity. Thepreferred neutral lipids in these carriers were uncharged lipids:triglycerides, which remain uncharged at all relevant pHs—pH between 1and 9.

In U.S. Pat. Nos. 4,950,656, 5,043,329, 5,763,422, and 5,955,451,saturated zwitterionic phospholipids in combination with saturatedtriglycerides were used to reduce GI toxicity, to increase thecyclohexane solubility of the NSAIDs, and to improve NSAID efficacy.U.S. Pat. Nos. 5,763,422, and 5,955,451 specifically demonstrated thataspirin (ASA):dipalmitoyl phosphatidylcholine (DPPC) solubility incyclohexane was enhanced by the addition of a triglyceride, tripalmtin.It was believed that the enhanced cyclohexane solubility was linked tothe improved NSAID efficacy and/or reduced ASA GI toxicity.

In publications and patents by Lichtenberger and coworkers, compositionsincluding a phospholipid and an NSAID were formed either by initiallydissolving the components in an organic solvent, such as methanol,ethanol or chloroform, and removing the solvent by distillation orevaporation: or the NSAID was dissolved in an aqueous solution at orabove the pKa of the NSAID and to a phospholipid film, followed bylyophilization if a solid product was required. These processes allowthe two components to chemically interact to form associated complexes.These processes most often used a phosphatidylcholine (PC) as thephospholipid either synthetically prepared such asdipalmitoylphosphatidylcholine (DPPC) or as a purified or semipurifiedPC compound.

More recently, in U.S. Pat. No. 6,451,339, Patel et al. disclosedcompositions and for improved delivery of hydrophobic agents, where thecompositions are substantially triglyceride-free and include acombination of a hydrophilic surfactant and a hydrophobic surfactant.

While these patents and applications disclose compositions and methodsfor preparing the compositions, where the compositions are effective inreducing the GI toxicity of NSAIDs, the patents and applications fail todisclose any information for the preparation of carrier that possess theability to target the release of NSAIDs into different parts of the GItract. Targeted release of biologically active agents exploiting thedifferential pH profile of the GI tract has been disclosed using variouspH sensitive polymers as coatings for acid labile drugs and drugs havingupper gastrointestinal toxicity. However, this approach has been limitedby stochastic pharmacokinetics and marked food effects (Leonards, J. R.and G. Levy. JAMA 193: 99-104, 1965, Bogentoft, C., I. Carlsson, et al.,European Journal of Clinical Pharmacology, 14(5), 351-355, 1978.

Thus, there is a need in the art for new and novel carriers andcompositions including the carriers that are capable of targeted releaseof active agents into different areas of the GI tract and other tractssuch as the urinary or reproductive tracts. There is also a need in theart for carriers and compositions including the carriers that arecapable of a targeted release and/or pH dependent release of an activeingredient, where the targeted and/or pH dependence conforms to atargeting profile and/or pH profile of the tract in the body of ananimal, mammal or human so that biologically active agents such asNSAIDs are released selectively in the tract such as into the duodenumor the small intestine and not the stomach of the GI tract, i.e., thecarriers release the biologically active agents slowly and inefficientlyin low pH environments such as gastric fluid, but release thebiologically active agents rapidly and efficiently at higher pHenvironments (e.g., pH values between 4 and 5) such as the upperduodenum, and even higher pH environments (e.g., pH values between 7 and8) in the presence of bile acids in small intestinal fluid.

SUMMARY OF THE INVENTION

Overview

The carriers of this invention and compositions including the carriersof this invention possess the capability of targeted release of abiologically active agent into a selected region of a targeted tissue,organs, or tracts, such as release into a region of the gastrointestinal(GI) tract, urinary tract, reproductive tract, or other tracts that havemucosal gels. Carrier-mediated targeted release is particularly usefulfor active ingredients that are: (a) injurious to the upper GI tract(esophagus, stomach, and duodenumn), (b) acid labile, (c)impermeable/insoluble compounds GI fluids, (d) susceptible to first passmetabolism, and (e) cause stomach irritation, upset, or dyspepsia. Incertain embodiments, the targeted release is a pH dependent release sothat the biologically active agent(s) is(are) released minimally at lowpH of the stomach (e.g., a pH less about 3-<pH 3) and are efficientlyreleased at higher pH of the upper duodenum (e.g., at pH greater than toor equal to 4-≧pH 4). In certain embodiments, the targeted release is apH dependent release so that the active agent(s) is (are) releasedminimally at low pH of the stomach (e.g., a pH less about 3-<pH 3) andupper duodenum (e.g., at pH greater than to or equal to 4 to 5), and areefficiently released at the higher pH of the small intestine in presenceof high concentration of bile. In certain embodiments, the pH dependentrelease of the active agent(s) is due to the inclusion in the carrier ofpH dependent release agents such as at least one oil soluble or misciblecompound including at least one ionizable group such as a carboxylicacid group, hydroxy group, amino group, amide groups, or other similarlyionizable groups. In other embodiments, the at least one ionizable groupincludes at least one carboxylic acid group or at least one oil solubleor miscible compound including at least one carboxylic acid group. Inother embodiments, the compounds including at least one carboxylic acidgroup are fatty acids sometimes referred to herein as free fatty acidsto fully distinguished these acids from the ester group of mono-, di,and tri-glycerides. Fatty acids are particularly useful for tailoredrelease of biologically active agents along the GI tract and othertracts having a pH profile, because most fatty acid are nonionized orneutral at low pH (e.g., gastric fluid pH), but become ionized at higherpH (e.g., intestinal fluid pH), which enables them to selectivelydeliver a biologically active agent payload. We present hereinpartitioning data, dissolution data, Fourier Transform Infra Red (FTIR)spectrometry data, and animal data that demonstrate the targeted releaseof NSAIDS, the pH dependent release of NSAIDs, and the efficacy of thesetargeted NSAID release, and/or pH dependent release carriers in mammals.These data clearly demonstrated that the carriers of the invention areideally suited for the targeted release of NSAIDs into different regionsof the GI tract. The partitioning data and the animal toxicity datademonstrated that these carriers are effective at targeting the releaseof aspirin in a pH dependent manner and that the targeted releaseselectively to the small intestine is efficient in reducing aspiringastric toxicity. The data also showed that the targeted and/or pHdependent release agents are operable even in the presence of othercomponents at relatively low and relatively high levels such asphospholipids, triglycerides, etc. The data also showed that thetargeted and/or pH dependent release characteristics of the carriers ofthis invention are effective for different NSAIDs and NSAID classes. Asthese NSAIDs are all weak acids, the efficacy of these compositions todemonstrate targeted and/or pH dependent release of different NSAIDs,strongly supports the capability for the carriers of this invention toalso be useful for the targeted and/or pH dependent release of otherpharmaceuticals and/or nutraceuticals. The data also showed that therelease characteristics of the carriers may be designed such that thebiologically active agent(s) is(are) released at low pH instead ofhigher pH so that the active agent may be targeted to tissue in contactwith low pH environments such as the stomach. Thus, the carriers of thepresent invention produce new, novel and readily tailored active agentcompositions having unique active agent release characteristics, uniqueactive agent efficacies, and/or unique active agent GI bioavailabilityand/or toxicity. As this targeted release of the active agents from thelipid matrix appears to be due to ionization state of the targetedrelease agents in the carrier relative to pH and other physiologicalmilieu of in selected regions of the tracts such as the GI tract,targeted release of any biologically active agent may be possible.

Carriers

Embodiments of the present invention provide carriers that possess thecapability for targeted active agent release and/or pH dependent activeagent release. The carriers generally include at least one targetingrelease agent, where the agent is capable of releasing an active agentor plurality of active agents in a targeted manner. In certainembodiments, the targeting release agents are pH dependent releaseagents that release the active agents in a pH dependent manner. Thecarriers may also include other biocompatible agents to modulate thedesired release and/or dissolution characteristics or to modify and/oralter other properties of the carrier and/or biologically active agents.Besides targeting the release for example in a pH dependent manner, thecarriers and/or components thereof may also modify and/or alter thechemical properties, physical properties, and/or behavior of the activeagents in tissues and/or organs, when administered to an animal, mammal,or human.

Embodiments of the present invention provide carriers capable of pHdependent release of an active agent or plurality of active agents,where the carriers include at least one pH dependent release agent suchas at least one oil soluble or miscible compound including at least oneionizable group such as a carboxylic acid group, hydroxy group, aminogroup, amide groups, or other similarly ionizable groups. In otherembodiments, the carriers include at least one carboxylic acid group orat least one oil soluble compound including at least one carboxylic acidgroup are free fatty acids.

Compositions

Embodiments of the present invention provide compositions including acarrier of this invention and an effective amount of at least onebiologically active agent, where the carrier is designed to effect atargeted release of the active agents and/or to modify and/or alter thechemical properties, physical properties, and/or behavior of the activeagents in tissues and/or organs, when administered to an animal, mammal,or human.

Embodiments of the present invention provide compositions including acarrier of this invention and an effective amount of at least onepharmaceutical agent and/or nutraceutical agent, where the carrier isdesigned to effect a targeted release of the pharmaceutical agentsand/or nutraceutical agents and/or to modify and/or alter the chemicalproperties, physical properties, and/or behavior of the agents intissues and/or organs, when administered to an animal, mammal, or human.

The above compositions may be in the form of a solution of the activeagents in the carrier, a suspension of the active agents in the carrier,where some of the active agents may be dissolved in the carrier, asuspension of the active agents in the carrier, where no active agent isdissolved in the carrier, a paste of the active agents in the carrier,or any other mixture or combination of the active agents in the carrieror surrounded by the carrier. The active agents may be present in thecarrier in an amount sufficient to produce a paste like suspension, acoated solid material such as coated crystals or coated micro or nanoparticles, where the coating may be from a monolayer to millimeters inthickness, a matrix of coated solid material, or any other formincluding a carrier of this invention and one or more active agents.

Methods for Making

Embodiments of the present invention provide methods for making thecarriers of this invention by mixing desired components together underconditions of temperature, pressure, and time sufficient in the presenceor absence of a solvent system to form a carrier having tailored activeagent release properties and/or tailored active agent interactionproperties. If a solvent system is used, the solvent is removed bydistillation and/or evaporation.

Embodiments of the present invention provide methods for making thecompositions of this invention by contacting a carrier of this inventionand an effective amount of at least one active agent under conditions oftemperature, pressure, and time sufficient in the present or absence ofa solvent system to form a composition having tailored active agentrelease properties and/or tailored active agent interaction properties.If a solvent system is used, the solvent is removed by distillationand/or evaporation and this method is sometimes referred to as thesolvation/evaporation method. In the absence of a solvent system, theactive agents are simply admixed with the carrier under conditions oftemperature, pressure, and time sufficient to form the designedcomposition and this method is sometimes referred to as the admixmethod. In certain embodiments, the active agents comprise at least onepharmaceutical agent and/or at least one nutraceutical agent. It shouldbe recognized by an ordinary artisan that the admix method reduces stepand eliminates any concern for trace solvent and could includeadvantages such as lowered manufacturing cost, environmentalmanufacturing concerns, etc. Alternatively, certain formulations maybenefit from solvation of the ingredients.

Methods for Using

Embodiments of the present invention provide methods for administeringcompositions of this invention, where the method comprises administeringa composition of this invention including a carrier and an effectiveamount of at least one active agent to a human, mammal, or animal, wherethe effective amount is sufficient to illicit a desired response. Themode of administration may be oral administration, sublingual or rectaladministration, or esophageal, gastric, intestinal instillation viaendoscopy. In certain embodiments, the administration may be topicalsuch as administration into ophthalmic, urinary, the reproductive, orother tract, tissue, or organ for which topical administrationrepresents an effective treatment methodology.

Methods for Screening

Embodiments of the present invention also provide methods for screeningactive agents such as pharmaceutical agents and/or nutraceutical agents,where the method comprises forming a composition including a test activeagent in a carrier of this invention. Once the composition is formed,the composition is placed in a differential solubility system. Onceadded to the differential solubility system, the method includesdetermining the partitioning coefficient of the active agent between thetwo immiscible solutions or solvents. To determine the relative release,solubility, and partitioning across the relatively pure hydrophobicmucosa or epithelial membranes of the stomach or duodenum, a two phasesystem comprised of cyclohexane and simulated gastric fluid (e.g., 0.1HCl) or cyclohexane and upper duodenal fluid (e.g., pH 4.5 buffer) maybe used. To determine the partitioning across epithelial, cellular, orintracellular membranes of mixed polarity of the stomach or duodenum, atwo phase system comprised of octanol and simulated gastric fluid (e.g.,0.1 HCl) or octanol and upper duodenal fluid (e.g., pH 4.5 buffer) maybe used. To determine the relative release, solubility, and partitioningacross the relatively more hydrophilic mucosal surface than the stomach,a two phase system comprised of octanol and simulated intestinal fluidscontaining digestive enzyme and lipid emulsifying agents (e.g., pH 7.2buffer with 1% Pancreatin and 20 mM cholic acid) may be used.Embodiments of the screening method may also include varying the pH ofthe aqueous media and determining the partitioning coefficient atdifferent pH values to test the pH dependent partitioningcharacteristics of the active agent in the carrier. We believe that thedifferential partitioning coefficients are an indirect measure of theability to target the delivery of the active agent from a given carrierso that carrier properties may be tailored for a given active agentdelivery profile such as a targeted delivery of an active agent in theGI tract.

Methods of Testing pH Dependent Release Capabilities

Embodiments of the present invention also provide methods for testingactive agents such as pharmaceutical agents and/or nutraceutical agentsfor pH dependent release from a carrier of this invention, where themethod comprises forming a composition including a test active agent ina carrier of this invention. Once the composition is formed, thecomposition is filled into hard shell capsules. Once the composition isfilled into the capsules, the capsules are placed in a plurality ofdissolution buffers having different pH values and/or differentdigestive enzyme and/or bile acid levels, measuring the rate ofdissolution in the different buffers and determining the pH dependentrelease properties of the test active agent in the carrier. We believethat the dissolution data permits the preparation of compositionsdesigned to release the active agent at a desired location along a tractof an animal, mammal, or human tract such as the GI tract.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention can be better understood with reference to the followingdetailed description together with the appended illustrative drawings inwhich like elements are numbered the same:

pH Dependent Release of Biologically Active Agents

FIG. 1 depicts partitioning (Log P) data for acetylsalicylic acid (ASA)and soy derived free fatty acid (FFA) compositions at 10:1, 1:1 and 1:10weight ratios, prepared simply by admixing and heating at 35° C. for 30minutes, to an ASA triple strength lecithin product (ASA:Phosal 35 SB)in a 1:1 weight ratio and 100% ASA. The triple strength lecithin product(P35) is Phosal 35SB. Equivalent amounts of aspirin were used in eachformulation tested for Log P_(cyclohexane/0.1N HCl.) ASA concentrationwas measured in the respective solvents by HPLC. Data are mean±SD ofthree replicate determinations.

FIG. 2 depicts partitioning (Log P) data for binary ratio of ASA and FFAat 1:1 weight ratios were prepared simple admixture and heating 35° C.for 30 min in creating aspirin suspension of ASA in soy FFA at two pHvalues comparted to ASA:Phosal 35 SB is a 1:1 weight ratio of aspirinand triple strength lecithin product (Phosal 35 SB). Equivalent amountof aspirin in the form of various formulations were tested for LogP_(cyclohexane/0.1N HCl.) ASA concentration was measured in therespective solvents by HPLC at the indicated pHs. Data are mean±SD ofthree replicate determinations.

FIG. 3 depicts partitioning (Log P) data for ASA:FFA carriers including1 wt. %, 5 wt. %, and 10% w/w PC compared to ASA:P35 is a 1:1 weightratio of Aspirin alone, where P35 (Phosal 35SB). Equivalent amounts ofeach preparation was tested for Log P_(cyclohexane/0.1N HCl.) Data aremean and SD of triplicate determinations. The formulation were preparedby admixing with aspirin on 1:1 weight basis in to the carrier.

FIG. 4 depicts dissolution profiles of immediate release aspirin tabletsat various pH levels. The data are mean±standard deviation (SD) ofreplicate determinations.

FIG. 5 depicts dissolution profiles of the triple strength lecithincarrier-ASA composition filled capsules at various pH levels. The dataare mean±standard deviation (SD) of replicate determinations.

Free Fatty Acids in Lecithin Oil Mediate pH Dependent Release ofBiologically Active Agents

FIG. 6 depicts dissolution of aspirin (ASA) compared to carries with andwithout free fatty acids (FFAs). The data are mean±standard deviation(SD) of replicate determinations.

Targeted Release of Biologically Active Agents Along the GI Tract

FIG. 7 depicts dissolution profiles in “simulated gastric fluid” (0.1 NHCl) pH 1 at 150 rpm. The data are mean±standard deviation (SD) ofreplicate determinations.

FIG. 8 depicts dissolution profiles in “simulated duodenal fluid” pH 4.5at 150 rpm. The data are mean±standard deviation (SD) of replicatedeterminations.

FIG. 9 depicts dissolution profiles in “simulated intestinal fluid” pH 7at 150 rpm. The intestinal fluid is a phosphate buffer, supplementedwith 1% pancreatin, and 20 mM cholic acid, pH 7. The data aremean±standard deviation (SD) of replicate determinations.

FIGS. 10A&B depict a side by side comparison of average dissolutionprofiles of 0 wt. % PC and 2.5 wt. % PC formulations in different media:simulated gastric, duodenal and intestinal fluid, and a phosphatebuffer, pH 6.8. The data are mean±standard deviation (SD) of replicatedeterminations.

pH Profile and General Composition of the Luminal Fluid in Upper GITract

FIG. 11 depicts a drawing of the human upper GI tract including thestomach and small intestine (duodenum, jejunumn, and ileum) indicatingthe pH ranges for the different regions of the upper GI Tract.Generally, gastric pH is acidic. Progressively distal to the stomach,the small intestine become more alkaline largely due to pancreaticsecretions. The alkaline pH and high concentration of bile acids,particularly after a meal, in the jejunum and ileum enableemulsification/digestion of lipids.

Targeted Release of Biologically Active Agents Along the GI TractImproving GI Safety

FIG. 12 depicts gastric lesions in rats treated with once daily 40 mg/kgof aspirin from the following AC1, P1, P2, and AC2 Formulas or negativecontrol (NAC).

FIG. 13 depicts luminal gastric and intestinal hemoglobin following3-day treatment with NAC, AC1, P1, P2, and AC2.

Use of Carriers to Increase Bioavailability of Poorly PermeableBiologically Active Agents

FIG. 14 depicts FTIR spectra of aspirin in various carriers.

FIG. 15 depicts ASA partitioning in an octanol/0.1 N HCl system usingcarriers having different FFA:TG ratios ranging from 100:0 to 0:100 inincrements of 20.

Generalizability of Carrier-Targeted Release to all Weak AcidBiologically Active Agents Salicylic Acid (SA)

FIG. 16 depicts partitioning at low and at neutral pH for salicylic acid(SA) and SA Formulas A, C, E, and G.

FIG. 17 depicts two stage dissolution profiles in pH 1 “simulatedgastric fluid” then in pH 7.2 “simulated intestinal fluid” at 75 RPM forsalicylic acid in various carriers.

Naproxen (NAP)

FIG. 18 depicts partitioning at pH 1 and at pH 7 for naproxen acid (NAP)unmodified and in NAP Formulas A, C, E, and G.

Indomethacin (INDO)

FIG. 19 depicts partitioning at pH 1 and at pH 7 for indomethacin (INDO)unmodified and in INDO Formulas A, C, E, and G.

Mefenamic Acid (MFA)

FIG. 20 depicts partitioning at pH 1 and at pH 7 for mefenamic acid(MFA) and in MFA Formulas A, C, E, and G.

DEFINITIONS OF TERMS

The following terms will have the meanings set forth below, which may ormay not correspond to their generally accepted meaning:

General Terms

The term “mixture” means a blend of one or more ingredients, where theingredients may interact at the molecular level, e.g., a homogeneousmixture is a mixture, where the ingredients are uniformly andhomogeneously distributed, while an inhomogeneous mixture is a mixture,where the ingredients are not uniformly and homogeneously distributed.

The term “combination” means one or more ingredients that are combined,but not mixed.

The term “substantially” means that the attribute, condition or value iswithin about 10% of the indicated value. In other embodiments, the termis within about 5% of the indicated value. In other embodiments, theterm is within about 2% of the indicated value. In other embodiments,the term is within about 1% of the indicated value.

The term “essentially free” or “substantially free” means compositionsthat include less than or equal to about 5 wt. % of a given ingredient.In certain embodiments, the terms means less than or equal to about 2wt. %. In other embodiments, the terms means less than or equal to about1 wt. %. In other embodiments, the terms means less than or equal toabout 0.5 wt. %. In other embodiments, the terms means less than orequal to about 0.1 wt. %. In other embodiments, the terms means lessthan or equal to about 0.05 wt. %. In other embodiments, the terms meansless than or equal to about 0.01 wt. %. In other embodiments, the termsmeans less than or equal to about 0.005 wt. %. In other embodiments, theterms means less than or equal to about 0.001 wt. %. In otherembodiments, the terms means less than or equal to about 0.0005 wt. %.In other embodiments, the terms means less than or equal to about 0.0001wt. %. Such ingredient may include, without limitation, water, solvents,or any other ingredient that is to be substantially excluded from thedesired composition.

The term “relatively high concentration” means that the pharmaceuticalor nutraceutical agents comprise greater than or equal to about 50 wt. %of the final composition. In certain embodiments, the term means thatthe pharmaceutical or nutraceutical agents comprise greater than orequal to about 55 wt. % of the final composition. In certainembodiments, the term means that the pharmaceutical or nutraceuticalagents comprise greater than or equal to about 60 wt. % of the finalcomposition. In certain embodiments, the term means that thepharmaceutical or nutraceutical agents comprise greater than or equal toabout 65 wt. % of the final composition. In certain embodiments, theterm means that the pharmaceutical or nutraceutical agents comprisegreater than or equal to about 70 wt. % of the final composition. Incertain embodiments, the term means that the pharmaceutical ornutraceutical agents comprise greater than or equal to about 75 wt. % ofthe final composition. In certain embodiments, the term means that thepharmaceutical or nutraceutical agents comprise greater than or equal toabout 80 wt. % of the final composition. In certain embodiments, theterm means that the pharmaceutical or nutraceutical agents comprisegreater than or equal to about 85 wt. % of the final composition.

The term “major component” means a component present a composition in anamount of at least 33 wt. % based on 100 wt. % formulations.

The term “association complex” or “associated complex” means anon-covalent association between two or more compounds, where thecompounds are held together by non-covalent chemical and/or physicalinteractions including hydrogen bonding, ionic bonding, dipolarinteractions, hyperpolarizible interactions, van der Waals interaction,electrostatic interaction, a polar bonding or interaction, or any otherchemical and/or physical attractive interaction. For example, NSAIDs andzwitterionic phospholipids form associated complexes.

The term “non-covalent interactions” means chemical and/or physicalinteractions including hydrogen bonding, ionic bonding, dipolarinteractions, hyperpolarizible interactions, van der Waals interaction,electrostatic interaction, a polar bonding or interaction, or any otherchemical and/or physical attractive interaction.

The term “hydrophilic” means a compound having a strong affinity forwater, tending to dissolve in, mix with, or be wetted by water.

The term “hydrophobic” means a compound lacking affinity for water;tending to repel and not absorb water; tending not to dissolve in or mixwith or be wetted by water.

The term “zwitterion” means a molecule that has a positively charged anda negatively charged functional group at biological pHs.

The term “anion” means a molecule that has an overall negative charge atbiological pHs.

The term “cation” means a molecule that has an overall positive chargeat biological pHs.

The term “relatively hydrophobic barriers” means any external, internal,cellular or sub-cellular barrier which has hydrophobic properties, whichgenerally resists or reduces transport and/or partitioning ofhydrophilic reagents across the barrier. Such barriers include, withoutlimitation, a mucosal gel layer (e.g., gastric, duodenal, or colonicmucosal gel layers, vaginal mucosal gel layers, esophagus mucosal gellayers, nasal mucosal gel layers, lung mucosal gel layers, etc.), aplasma lemma (cellular membrane), the blood-brain barrier, placentalbarrier, testicular barrier, or any other barrier of a human, mammal oranimal, through which partitioning and/or transporting of hydrophobicmaterials more easily occurs than hydrophilic materials.

The term “residual water” means water remaining in components used tomake the compositions of this invention. Generally, the residual watercomprise a small impurity in the components of the compositions of thisinvention.

The term “minimal residual water” means that the compositions of thisinvention include less than about 5 wt. % residual water. In certainembodiments, the compositions of this invention include less than about4 wt. % residual water. In certain embodiments, the compositions of thisinvention include less than about 3 wt. % residual water. In certainembodiments, the compositions of this invention include less than about2 wt. % residual water. In certain embodiments, the compositions of thisinvention include less than about 1 wt. % residual water.

The term “low moisture” means that the compositions only includeresidual water found in the components used to make the compositions ofthis invention.

The terms “modify, alter, and/or augment chemical and/or physicalproperties and/or behavior” means that the carriers of the presentinvention are designed to form hydrophobic matrices in which an activeagent is mixed as a solid or liquid (depending on the nature of theactive agent). These hydrophobic matrices operate to modify, alter oraugment chemical and/or physical characteristics of the active agent byproviding an immiscible/different environment compared to an aqueousbiofluid such as blood, gastric fluids, duodenal fluids, smallintestinal fluids, large intestinal fluids, vaginal fluids, rectalsolids/fluids, or any other biofluid setting up a situation where theactive agent is free to partition between the two immiscibleenvironments. Additionally, properties of the carriers of this inventionsuch as viscosity, lipophilicity, hydrophobicity, dispersibility,dispensability, softening temperature, melting temperature, etc. alsoact to modify, alter or augment the rate of partitioning of the activeagent by sequestering the active agent in the immiscible carrier untilthe carrier matrix is dispersed to small enough particles to facilitatemass transfer from the immiscible carrier to the biofluid. For solidactive agents sequestered in a carrier matrix of this invention, anadded reduction in partitioning rate ensues because the active agentmust dissolve out of the matrix as the particle size of the matrixreduces in the biofluid due to mechanic actions of the tissue and/ororgan and/or due to biochemical processes occurring in the tissue and/ororgan.

The term “targeted manner” means that an active agent is targeted forrelease into a desired biological environment.

The term “pH dependent manner” means that pH affects how the carriers ofthe present invention operate to modify, alter or augment chemicaland/or physical characteristics of the active agent by providing animmiscible/different environment compared to an aqueous biofluid such asblood, gastric fluids, duodenal fluids, small intestinal fluids, largeintestinal fluids, vaginal fluids, rectal solids/fluids, or any otherbiofluid setting up a situation where the active agent is free topartition between the two immiscible environments. Additionally,properties of the carriers of this invention such as viscosity,lipophilicity, hydrophobicity, dispersibility, dispersibility, softeningtemperature, melting temperature, etc. also act to modify, alter oraugment the rate of partitioning of the active agent by sequestering theactive agent in the immiscible carrier until the carrier matrix isdispersed to small enough particles to facilitate mass transfer from theimmiscible carrier to the biofluid. For solid active agents sequesteredin a carrier matrix of this invention, an added reduction inpartitioning rate ensues because the solid must dissolve out of thematrix as the particle size of the matrix reduces in the biofluid due tomechanic actions of the tissue and/or organ and/or due to biochemicalprocesses occurring in the tissue and/or organ. Thus, the pH of thebiofluid changes the rate at which the immiscible carrier matrixdisperses in the biofluid and the mass transfer rates of the activeagents out of the carrier matrix. For weak acid active agents and weakbase active agents, the carrier may be designed to reduce release of theactive agent until the pH of the biofluid is at or near (within about 1pH unit or less) of the pK_(a) or pK_(b) of the active agent. For a weakacid active agent, the carrier reduces release of the active agent inlow pH environments such as in gastric fluid, which showing increasedrelease in pH environments at or near (within about 1 pH unit or less)of the pK_(a) of the weak acid active agent.

The term “one or more”, “at least one”, “one . . . or a plurality of . .. ” all mean a singular article or more than one articles.

Agents and Compounds

The term “active agent” or “biologically active agent” or “activeingredient” or “biologically active ingredient” means any pharmaceuticalagent or any nutraceutical agent as defined by the United State Food andDrug Administration (FDA).

The term “pharmaceutical agent” means any compound or composition thathas been or will be approved for human, mammal, and/or animaladministration for treating some malady, disease, syndrome, dysfunction,etc.—generally drugs approved for example by the FDA.

The term “nutraeceutical agent” means any compound or composition forhuman, mammal, and/or animal administration for nutritionalsupplementation or other uses.

The term “weak acid active agents” and “weak base active agents” areactive agents that are only partially ionized in aqueous solutions andthe extent of ionization depends on the pH of the aqueous solution.

The term “anti-inflammatory drugs” mean any of a variety of drugs thatreduce or inhibit inflammation in tissue, organs, or the like.Anti-inflammatory drugs including non-steroidal, anti-inflammatory drugs(COX1 and/or COX2 inhibitors), drugs for treating irritable boweldisorder or disease (IBD) represents a family of ulcerative diseasesincluding Ulcerative Colitis and Crohn's Disease that affect the colonand distal small bowel, and other drugs that have anti-inflammatoryactivity in humans, mammals and/or animals. The present targeteddelivery systems may also find utility in treating conditions evidencinga pH imbalance in animal, mammals, and human GI, urinary, andreproductive tracts.

The term “NSAID” means any of a variety of drugs generally classified asnon-steroidal, anti-inflammatory drugs, including, without limitation,ibuprofen, piroxicam, salicylate, aspirin, naproxen, indomethacin,diclofenac, COX2 inhibitors or any mixture thereof.

The term “oil” means any of numerous mineral, vegetable, and syntheticsubstances and animal and vegetable fats that are generally slippery,combustible, viscous, liquid, or liquefiable at room temperature,soluble in various organic solvents such as ether but not in water.

The term “lipid” means any of a group of organic compounds includingfats, oils, waxes, sterols, mono-glycerides, di-glycerides, andtriglycerides that are insoluble in water but soluble in nonpolarorganic solvents and are oily to the touch.

The term “neutral lipid” (NL) means a non-charged, non-phosphoglyceridelipid including mono-glycerides, di-glycerides, triglycerides or mixturethereof. In some embodiments, the term neutral lipid refers exclusivelyto tri-glycerides (TGs).

The term “phospholipid” (PL) means any biocompatible phospholipid.

The term “zwitterionic phospholipid” means any phospholipid bearing apositive and an negative charge at biological pHs including, but notlimited to, phosphatidylcholine, phosphatidylserine,phosphalidylethanolamine, sphingomyelin and other ceramides, as well asvarious other zwitterionic phospholipids.

The term “biocompatible” means being compatible with living cells,tissues, organs, or systems, and posing no, minimal, or acceptable riskof injury, toxicity, or rejection by the immune system of a human,mammal, or animal.

The term “biocompatible agent” means any compound that is compatiblewith living cells, tissues, organs, or systems, and posing no risk ofinjury, toxicity, or rejection by the immune system of a human, mammal,or animal. There are a number of classes of biocompatible agentssuitable for use in the invention including hydrophobic biocompatibleagents, biocompatible oils, pH dependent biocompatible release agentssuch as biocompatible fatty acids or biocompatible fatty polyacids, andlecithin oils.

The term “biocompatible oil” means any oil that is compatible withliving cells, tissues, organs, or systems, and posing no risk of injury,toxicity, or rejection by the immune system of a human, mammal, oranimal. In certain embodiments, biocompatible oils are any oil that hasbeen approved for human consumption by the FDA or other governmentalagents or approved for of a human, mammal, or animal consumption, wherethe compound may be a solid or liquid at room temperature or biologicaltemperatures. In certain embodiments, the term means any oil that is afluid at biological temperatures. In other embodiments, the term meansany oil that is a fluid at room temperature.

The term “biocompatible fatty acid or biocompatible free fatty acid”means any fatty acid or free fatty acid (FFA) that is compatible withliving cells, tissues, organs, or systems, and posing no risk of injury,toxicity, or rejection by the immune system of a human, mammal, oranimal. In certain embodiments, biocompatible fatty acids aremono-carboxylic acids. In certain embodiments, the biocompatible fattyacids have at least 8 carbon atoms. In other embodiments, thebiocompatible fatty acids have at least 10 carbon atoms. In otherembodiments, the biocompatible fatty acids have at least 12 carbonatoms. In other embodiments, the biocompatible fatty acids have at least14 carbon atoms. In other embodiments, the biocompatible fatty acidshave at least 16 carbon atoms. In other embodiments, the biocompatiblefatty acids have at least 18 carbon atoms. In certain embodiments, thebiocompatible fatty acids may be unsaturated fatty acids. In certainembodiments, the biocompatible fatty acids may be saturated fatty acids.In certain embodiments, the biocompatible fatty acids may be a mixtureof saturated and unsaturated fatty acids. The term “free fatty acid” isused sometimes as a term to fully distinguish between a fatty acid and afatty acid ester of a mono-, di-, and tri-glyceride.

The term “biocompatible fatty acid ester” means any fatty acid esterthat is compatible with living cells, tissues, organs, or systems, andposing no risk of injury, toxicity, or rejection by the immune system ofa human, mammal, or animal. In certain embodiments, the biocompatiblecarboxylic acid esters are esters of mono-alcohols or polyols.

The term “biocompatible fatty acid salt” means any salt of abiocompatible carboxylic acid.

In certain embodiments, the salts are salts of mono-carboxylic acids.

The term “biocompatible fatty poly acids” means any biocompatiblecompound having more than one carboxylic acid moiety per compound thatis compatible with living cells, tissues, organs, or systems, and posingno risk of injury, toxicity, or rejection by the immune system of ahuman, mammal, or animal. In certain embodiments, the biocompatible polyacids have at least 8 carbon atoms. In other embodiments, thebiocompatible poly acids have at least 10 carbon atoms. In otherembodiments, the biocompatible poly acids have at least 12 carbon atoms.In other embodiments, the biocompatible poly acids have at least 14carbon atoms. In other embodiments, the biocompatible poly acids have atleast 16 carbon atoms. In other embodiments, the biocompatible fattyacids have at least 18 carbon atoms. In certain embodiments, thebiocompatible fatty acids may be unsaturated fatty acids. In certainembodiments, the biocompatible fatty acids may be unsaturated fattyacids. In certain embodiments, the biocompatible fatty acids may besaturated fatty acids. In certain embodiments, the biocompatible fattyacids may be a mixture of saturated and unsaturated fatty acids.

The term “lecithin” means a yellow-brownish fatty substances derivedfrom plant or animal and that is defined as complex mixture ofacetone-insoluble phosphatides, which consist chiefly ofphosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, andphosphatidylinositol, combined with various amounts of other substancessuch as triglycerides, fatty acids, and carbohydrates, as separated fromthe crude vegetable oil source. It contains NLT 50.0% ofacetone-insoluble matter. In certain embodiments, the lecithin maycomprised of lipids esterified with unsaturated fatty acid side chains.In other embodiments, the lecithin may be comprised of lipids withsaturated lipids. In other embodiments, the lecithin may be comprised oflipids with mixtures thereof.

The term “crude lecithin” means a lecithin containing having about 10-15wt. % phosphatidylcholine.

The term “semi crude or triple strength lecithin” means a lecithin wherethe phosphatidylcholine content has been increased to 35 wt. % to about50 wt %.

The term “lecithin oil” means a liquid lecithin where lecithin issolubilized in oil and/or a free fatty acid. In certain embodiments,this lecithin oil is a semi crude or triple strength lecithinsolubilized in a triglyceride and/or a free fatty acid.

The term “a purified phospholipid” means a naturally extracted orsynthetic phospholipid having a purity above at least 90 wt. % ofphospholipids, a single compound, or a class of closely relatedphospholipids such as phosphatidylcholine, phosphatidylethanol amine,dipalmitoylphosphatidylcholine (DPPC), or other similar phospholipids.Purified phospholipids are not lecithin, but may be derived fromlecithin through extraction and purification.

The term “targeted biocompatible release agent” or “targeted releaseagent” means an agent that controls the release of one or more activeagents in a targeted manner, i.e., release the active agents into aparticular tissue or organ depending on the tissue or organ'sphysiological environment.

The term “pH dependent biocompatible release agent” or “pH dependentrelease agent” means a targeted release agent that controls the releaseof one or more active agents in a pH dependent manner. For example,fatty acids having between about 8 and about 50 carbon atoms, or fattypolyacids having between about 12 and about 50 carbon atoms will releaseone or more active agents in a pH dependent manner, when a compositionincluding a fatty acid or fatty polyacid is administered orally suchthat a low pH, the active agent is retained in the carrier by the fattyacid or fatty polyacid, but is released as the composition exits thestomach and the pH raised to about pH 7 in the upper intestines. The pHdependent biocompatible release agents are a subclass of the generalclass of biocompatible agents and in particular, hydrophobicbiocompatible agents.

The term “carrier” means a composition that is a base for active agentssuch as pharmaceutical and/or nutraceutical agents.

The term “hydrophobic carrier” means a composition that is a base foractive agents such as pharmaceutical and/or nutraceutical agents, wherethe carrier including one or more or at least one hydrophobicbiocompatible agents and where the carrier is immiscible in water.

The term “oil-based carrier” means an oil-based composition that is abase for active agents such as pharmaceutical and/or nutraceuticalagents. The oil-based carriers comprises one or more biocompatible oilsand/or biocompatible hydrophobic agents and is a water immiscible.

Methods of Administration

The term “internal administration”, “internally administered” or“parenteral administration” means administration via any technique thatadministers a composition directly into the blood stream, a tissue site,an organ or the like without first passing through the digestive tract.

The term “oral administration” or “oral administered” meansadministration via mouth.

The term “topical administration” or “topically administered” meansadministration onto a surface such as the skin, a mucosal gel layer(e.g., vaginal, rectal, ophthalmical, etc.), a tissue and/or organexposed during a surgical procedure, or any other exposed bodily tissue.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have found that unique carriers may be prepared forbiologically active agents such as pharmaceutical and/or nutraceuticalagents, where the carriers include one or a plurality of biocompatibletargeted release agents so that the carrier targets the release of theactive agents to a specific portion or specific portion of a tract in ananimal, mammal, or human such as the gastrointestinal (GI) tract, theurinary tract, the reproductive tract, or tissues such as ophthalmictissue. The inventors have also found that the carriers may be designedto include a sufficient amount of at least one biocompatible pHsensitive or dependent release agent so that the carriers release theactive agents such as pharmaceutical and/or nutraceutical agents in a pHdependent manner. The inventors have also found that pharmaceuticaland/or nutraceutical compositions may be formulated including a carrierof this invention and an effective amount of at least one pharmaceuticalagent and/or at least one nutraceutical agent, where the agents may bereleased in a targeted or tailored manner within a tract of the bodysuch as the GI tract. The inventors have found that the carriers of thisinvention may include pH dependent release systems that releasepharmaceutical and/or nutraceutical agents in a pH dependent mannertargeting different portions of a tract of the body such as the GI tractand due to the hydrophobic nature of the carriers and/or the carriercomponents, improving the ability of the agents to partition acrosshydrophobic mucosal barriers or membranes in pH dependent manner. Thecompositions of this invention are also well suited for the delivery ofbiologically active ingredients in a pH dependent manner due to pHchanges that occur in tissues, organs, or tracts in response to certainpre-disease or disease states.

As the population of the world and particularly the United States hasincreasing numbers of older citizens and citizens that are physicallyheavier than previous generations, the need for new delivery systems forbiologically active agents that are known to have certain adverseeffects such as adverse GI affects increases, especially fornon-steroidal, anti-inflammatory drugs (NSAIDs). NSAIDs are ubiquitouslyused drugs for managing pain, for reducing or managing cardiovasculardisease, for reducing platelet aggregation, for reducing fever, forreducing or preventing cancer, and for a number of other uses. However,NSAIDs have a major drawback, they all have, to some extent, the abilityto cause irritation, erosion, and/or ulceration of the stomach and upperGI tract. In recent years, Lichtenberger and coworkers have demonstratedthat associating NSAIDs with phospholipids are capable of greatlyreducing the GI toxicity of certain NSAID such as aspirin and ibuprofen.However, compositions including high amount of NSAID and high amount ofphospholipids are subject to breakdown over time due to hydrolysis, foraspirin, of the acetyl side chain and for phospholipids, of the fattyacid side chains. In an ongoing effort to construct improved deliverysystems for NSAIDs and any other pharmaceutical and/or nutraceuticalagents that requires targeted release or delivery of the NSAIDs oragents into desired portions of the GI tract, we have developed carriersystems that are immiscible with water and include at least one targetedrelease agent. We demonstrate herein that carrier including at least onetargeted release agent may be used to delivery one or more active agentsinto different portions of the GI tract. For example, if a given activeagent has a known adverse interaction with the stomach or other low pHbiological environments, the carriers may be designed so that the activeagent is not effectively released until the pH rises to a pH greaterthan about pH 3. In these carriers, the active agents release at pHvalues of less the pH 2 at a rate of less than about 20% in thirtyminutes, while the active agents release at pH values above about pH 3at a rate of greater than 80% in thirty minutes. These same targetedrelease carriers are also well-suited for acid sensitive active agents,where the release is designed for pH values greater the pH 5. We alsodemonstrate herein that carriers immiscible in water may be formulatedfor rapid release into low pH environments instead of releasing intohigher pH environments. Thus, the carriers of this invention may bedesigned to release active agents to any pH environment and potentiallyto any given biological environment.

We have found that the targeted release agents are any compound thatincludes at least one ionizable group such as a carboxylic acid group,hydroxy group, amino group, amide groups, or other similarly ionizablegroups, are immiscible in water or soluble in oils, and, for weak acids,have a pKa value greater than or equal to about pH 3.5. These targetedrelease agents are neutral and pH values below their pKa values,especially at pH values less than pH 2, and become ionized at pH valuesabove their pKa values. Thus at low pH (<pH 2), the targeted releaseagents behave simply as oils remaining immiscible in aqueous fluids andevidence minimal release of active agent in low pH fluid environments.But as the pH rises, the release agents become ionized and now act asactive surfactants causing a rapid dissolution of the carrier includingthe active agent in higher pH environments. Because the GI tract has apH profile starting at the stomach and proceeding to the largeintestines of increasing pH from a pH value in the stomach of about pH 1and about pH 3 to a pH in the duodenum between about pH 3 and pH 5 to pHvalues as high as pH 8 in the large intestines, using release agentshaving different pKa values, we can design a carrier that willefficiently and rapidly release an active agent only when the pH of theenvironment is at or greater than the pKa value of the release agents.We have also found that carriers of this invention may include from justa sufficient amount of the release agents to 100% of release agents. Wehave also found that other components such as neutral lipids,zwitterionic surfactants, excipients, and/or adjuvants may be added tothe carrier without significantly or adversely affecting the releaseproperties of the carrier. Thus, carriers including 100% of the releaseagents evidence similar partitioning profiles, dissolution profiles, andin vivo efficacies compared to carriers with small amounts or largeamount of other components including neutral lipids and phospholipids.

We have found that fatty acids represent one class of targeted releaseagents that are immiscible in water and have pKa values generallygreater than about pH 3 and are converted to surfactants throughionization at pH values at or above their pKa values. We have alsodiscovered that carriers may be tested to determine their potential useas targeted release carriers using partitioning studies of thecarrier/active agent compositions in bi-phasic systems, where one of thephases represent a low pH or aqueous environment and the other phaserepresents a hydrophobic environment. The partitioning data providespredictive information about the ability for a given carrier to releasea given active agent at a given pH. We have also discovered thatcompositions including a targeted release carrier of this invention anda given active agent may be tested for pH dependent releasecharacteristic by studying the release properties of the composition isvarious dissolution media, especially dissolution media having differentpH values so that the dissolution of the active agent may be determinedfrom pH 1 to pH 7 or higher. The dissolution profiles provide in vitrodata to predict the release characteristics a given system.

Embodiments of the present invention relates to compositions comprising:(1) a carrier including a sufficient amount of a pH dependent releasesystem, and (2) at least one biologically active agent, where thecarrier releases the biologically active agents in a pH sensitive mannercharacterized in that less than 20% of the biologically active agentsare released into a gastric fluid and greater than 50%/s of thebiologically active agents are released in an intestinal fluid having apH value greater than pH 3.

Embodiments of the present invention relates to compositions comprising:(1) a carrier including a sufficient amount of a pH dependent releasesystem, and (2) at least one biologically active agent, where thecarrier releases the biologically active agents in a pH sensitive mannercharacterized in that the biologically active agents are releasedminimally into stomach and efficiently released into an intestinalregion.

Embodiments of the present invention relates to compositions comprising:(1) a carrier including a sufficient amount of a pH dependent releasesystem, and (2) at least one biologically active agent, where thecarrier releases the biologically active agents in a pH sensitive mannercharacterized in that the biologically active agents are releasedminimally at a first pH and efficiently released at second pH.

Embodiments of the present invention relates to compositions comprising:(1) a carrier including a sufficient amount of a pH dependent releasesystem, and (2) at least one biologically active agent, where thecarrier releases the biologically active agents in a pH sensitive mannercharacterized in that the biologically active agents are releasedminimally into stomach and efficiently released into an intestinalregion having different concentrations and/or types of bile acids and/ordigestive enzymes.

In certain embodiments, the pH sensitive manner is characterized bydifferential release of the active agents into gastric fluid andintestinal fluid. In other embodiments, the biologically active agentsare substantially non-ionized at gastric fluid pH and become ionized asthe pH increases. In other embodiments, the pH dependent release systemcomprising a fatty acid or a plurality of fatty acids having at least 8carbon atoms. In other embodiments, the biologically active agents areselected from the group consisting of weak acid biologically activeagents, weak base biologically active agents, and mixtures orcombinations thereof. In other embodiments, the weak acid biologicallyactive agents are selected from the group consisting of a weak acidnon-steroidal anti-inflammatory drugs (NSAID) and mixtures of NSAIDs.

Embodiments of the present invention relates to pharmaceuticalcompositions comprising a carrier including a sufficient amount of a pHdependent release system, and at least one weak acid non-steroidalanti-inflammatory drug (NSAID), where the carrier releases the NSAIDs ina pH sensitive manner characterized in that less than 20% of thebiologically active agents are released into gastric fluid and greaterthan 50% of the biologically active agents are released in intestinalfluid having a pH value greater than pH 3, and where the biologicallyactive agents are substantially non-ionized at gastric fluid pH andbecome ionized as the pH increases. In other embodiments, the pHdependent release system comprising of a fatty acid or a plurality offatty acids having at least 8 carbon atoms.

Embodiments of the present invention relates to pharmaceuticalcompositions comprising a suspension of a weak acid non-steroidalanti-inflammatory drug (NSAID) agent or mixture of NSAIDs in a carriercomprising a sufficient amount of a pH dependent release system.

Embodiments of the present invention relates to pharmaceuticalcompositions comprising a suspension of a weak acid non-steroidalanti-inflammatory drug (NSAID) agent or mixture of NSAIDs in a carriercomprising a sufficient amount of at least one fatty acid having atleast 8 carbon atoms.

Embodiments of the present invention relates to methods of targeting abiologically active agent along the gastrointestinal (GI) tractcomprising the step of orally administering a composition comprising acarrier including a sufficient amount of a pH dependent release system,and at least one biologically active agent, where the carrier releasesthe biologically active agents in a pH sensitive manner characterized inthat less than 20% of the biologically active agents are released intogastric fluid and greater than 50% of the biologically active agents arereleased in intestinal fluid having a pH value greater than pH 3, andwhere the biologically active agents are uncharged at gastric fluid pHand charged at pH values greater than pH 3 or are unstable in fluidshaving a pH less than pH 3.

Embodiments of the present invention relates to carrier compositionscomprising a least one biocompatible targeted release agent, where thecarrier composition and/or its components are capable of controllablyreleasing at least one active agent into certain portions of thegastro-intestinal (GI) tract. In other embodiments, the biocompatibletargeted release agents comprise pH dependent release agents capable ofcontrollably releasing the active agents in a pH dependent manner. Inother embodiments, the biocompatible targeted release agents comprise pHdependent release agents capable of controllably releasing the activeagents into certain portions of the GI tract based on a pH of theportions. In other embodiments, the pH dependent release agents includebiocompatible fatty acid having at least 8 carbon atoms. In otherembodiments, the carrier further comprising at least one neutral lipid,where the neutral lipid is water immiscible. In other embodiments, theneutral lipids comprise mono-glycerides, diglycerides, triglycerides, ormixtures and combinations thereof, where the ester side chains have atleast 6 carbon atoms. In other embodiments, carrier further comprisingless than 10 wt. % of a phospholipid or a plurality of phospholipids.

Embodiments of the present invention relates to carrier compositionscomprising 100 wt. % of at least one biocompatible fatty acid having atleast 8 carbon atoms, and 0 wt. % to 100 wt. % at least one neutrallipid, where the carrier composition and/or its components are capableof controllably releasing at least one active agent into certainportions of the gastro-intestinal (GI) tract and where the wt. % may addto a value greater than 100. In other embodiments, the carriercomposition further comprising less than 10 wt. % of a phospholipid. Inother embodiments, the carrier composition further comprising less than5 wt. % of a phospholipid. In other embodiments, carrier compositionfurther comprising less than 2.5 wt. % of a phospholipid.

Embodiments of the present invention relates to compositions comprisinga carrier including a least one biocompatible targeted release agent,and an effective amount of at least one biologically active agent, wherethe carrier composition and/or its components are capable ofcontrollably releasing at least one active agent into certain portionsof the gastro-intestinal (GI) tract. In other embodiments, the carrierand/or its components modify and/or alter the chemical and/or physicalproperties and/or behavior of the at least one active agent in tissuesand/or organs reducing and/or altering tissue and/or organ toxicity,improving and/or altering bioavailability, and/or improving and/oraltering efficacy. In other embodiments, the carrier is capable ofreleasing the at least one active agent in a pH dependent manner. Inother embodiments, the biocompatible targeted release agent comprise atleast one biocompatible fatty acid having at least 8 carbon atoms.

Embodiments of the present invention relates to compositions comprisinga carrier including 100 wt. % of at least one biocompatible fatty acidhaving at least 8 carbon atoms, and 0 wt. % to 100 wt. % at least oneneutral lipid, where the neutral lipid is immiscible in water, where thewt. % may add to a value greater than 100, and an effective amount of atleast one biologically active agent, where the carrier compositionand/or its components are capable of controllably releasing at least oneactive agent into certain portions of the gastro-intestinal (GI) tract.In other embodiments, the carrier and/or its components modify and/oralter the chemical and/or physical properties and/or behavior of the atleast one active agent in tissues and/or organs reducing and/or alteringtissue and/or organ toxicity, improving and/or altering bioavailability,and/or improving and/or altering efficacy. In other embodiments, thecarrier further including less than 10 wt. % of a phospholipid. In otherembodiments, the carrier further including less than 5 wt. % of aphospholipid. In other embodiments, the carrier further including lessthan 2.5 wt. % of a phospholipid.

Embodiments of the present invention relates to compositions comprisinga carrier including 100 wt. % of at least one biocompatible fatty acidhaving at least 8 carbon atoms, and 0 wt. % to 100 wt. % at least oneneutral lipid, where the neutral lipid is immiscible in water, where thewt. % may add to a value greater than 100, and an effective amount of atleast one biologically active agent, where the carrier compositionand/or its components are capable of controllably releasing at least oneactive agent into certain portions of the gastro-intestinal (GI) tract.In other embodiments, the carrier and/or its components modify and/oralter the chemical and/or physical properties and/or behavior of the atleast one active agent in tissues and/or organs reducing and/or alteringtissue and/or organ toxicity, improving and/or altering bioavailability,and/or improving and/or altering efficacy. In other embodiments, thecarrier further including less than 10 wt. % of a phospholipid. In otherembodiments, the carrier further including less than 5 wt. % of aphospholipid. In other embodiments, the carrier further including lessthan 2.5 wt. % of a phospholipid.

Embodiments of the present invention relates to compositions comprisinga carrier including less than 8 wt. % of at least one biocompatiblefatty acid having at least 8 carbon atoms or greater than 14 wt. % of atleast one biocompatible fatty acid having at least 8 carbon atoms, andfrom 0 wt. % to 100 wt. % at least one neutral lipid, where the neutrallipid is immiscible in water, and from 0 wt. % to 100 wt. % of a leastone phospholipids, where the wt. % may add to a value greater than 100,and an effective amount of at least one biologically active agent, wherethe carrier composition and/or its components are capable ofcontrollably releasing at least one active agent into certain portionsof the gastro-intestinal (GI) tract. In other embodiments, the carrierand/or its components modify and/or alter the chemical and/or physicalproperties and/or behavior of the at least one active agent in tissuesand/or organs reducing and/or altering tissue and/or organ toxicity,improving and/or altering bioavailability, and/or improving and/oraltering efficacy.

Carriers

Embodiments of the present invention relates broadly to carriercompositions including at least one biocompatible targeted releaseagent. The carriers and/or their components modify and/or alter thechemical and/or physical properties and/or behavior of at least oneactive agent in tissues and/or organs reducing and/or altering tissueand/or organ toxicity, improving and/or altering bioavailability, and/orimproving and/or altering efficacy. In certain embodiments, the carriersand/or their components modify and/or alter the chemical and/or physicalproperties and/or behavior of at least one active agent in tissuesand/or organs in a pH dependent manner to reduce and/or alter tissueand/or organ toxicity, improve and/or alter bioavailability, and/orimprove and/or alter efficacy. In certain embodiments, the biocompatibleagents are hydrophobic.

The present invention relates broadly to carriers for active agentsincluding: (1) a biocompatible fatty acid or a plurality ofbiocompatible fatty acids, (2) optionally a biocompatible fatty acidester or a plurality of biocompatible fatty acid esters, (3) optionallya biocompatible oil or a plurality of biocompatible oils, (4) optionallya biocompatible fatty acid salt or a plurality of biocompatible fattyacid salts, (5) optionally a secondary complexing agent, and (6)optionally a protective system including agents to reduce and/oreliminate toxicities, irritations or side-effects. The carriers aregenerally viscous fluids capable of being orally administered, directlyadministered, internally administered and/or topically administered.

In certain embodiments, the carriers of this invention may also includeother components such as: (1) excipients, (2) adjuvants, (3) dryingagents, (4) antioxidants, (5) preservatives, (6) chelating agents, (7)viscomodulators, (8) tonicifiers, (9) flavorants and taste maskingagents, (10) colorants, (11) odorants, (12) opacifiers, (13) suspendingagents, (14) binders, and (15) mixtures thereof.

The carries are generally viscous fluids and the composition madetherefrom are generally solutions, pastes, semi-solids, dispersions,suspensions, colloidal suspensions or mixtures thereof and are capableof being orally administered, parenterally administered or topicallyadministered.

Fatty Acid Targeted Releases Agents

We also believe that the carriers and/or their components interact withcertain types of active agents to affect particle size, morphology,other physical characteristics, physical/chemical properties and/orbehavior and physical/chemical properties of the crystals of the activeagent in the carrier. In certain embodiments, the active agents areadded to the carrier at an elevated temperature, where the temperaturemay be up to the melting temperature of the active ingredient, but belowa decomposition temperature of any of the carrier components or activeingredients. The inventors believe that the augmented properties resultin increased bioavailability of the active agent once the pH of theenvironment is at or near the pK_(a) or pK_(b) of the pH dependentrelease agents and/or the active agents.

Secondary Complexing Agents

Embodiments of the carrier compositions may also include at least onesecondary agent capable of interacting with the active agents added tothe carrier. Embodiments of the carrier compositions may also include asecondary anti-toxicity system designed to reduce toxic side effects ofthe active agents. Embodiments of these carrier compositions aregenerally water free or essentially or substantially water free and/orsolvent free or essentially or substantially solvent free. Being oils,the carriers are water immiscible. We have found that therapeuticcompositions may be prepared by adding at least one therapeuticallyactive agent to a carrier of this invention with tailored properties,where the therapeutically active agent includes pharmaceutical agentsand/or nutraceutical agents. We have also found that pharmaceuticalcompositions may be prepared by adding at least one pharmaceutical agentto a carrier of this invention under conditions to form a pharmaceuticalcomposition having tailored properties. The inventors have also foundthat nutraceutical compositions may be prepared by adding at least onenutraceutical agent to a carrier of this invention to form anutraceutical composition having tailored properties. Embodiments ofthese compositions are water free or essentially water free and/orsolvent free or essentially solvent free, i.e., the compositions areimmiscible in biofluids in a pH dependent manner.

For pharmaceutical agents that have GI toxicity, the carriers of thisinvention may also include neutral lipids and/or phospholipids, e.g.,non-steroidal, anti-inflammatory drugs (NSAIDs) as the pharmaceuticalagents, where the neutral lipids and/or phospholipids are known toreduce the pathogenic effects of the NSAIDs, such as GI ulceration,bleeding, liver damage, kidney damage, and/or cardiovascular diseaseand/or side-effects such as; high blood pressure, atherosclerosis,thrombosis, angina pectoralis, strokes and myocardial infarction. Incertain embodiments, the carriers of this invention include free fattyacid (FFA) carriers in the absence or present of phospholipids, wherethe phospholipids reduce and/or eliminate pharmaceutical and/ornutraceutical toxicities, irritations or side-effects of certainpharmaceutical and/or nutraceutical agents such as NSAIDs, while thephospholipid free carriers afford direct targeted release of the NSAIDresulting in released GI toxic side effects.

Compositions

Embodiments of the present invention relates broadly to compositionsincluding a carrier of this invention and an effective amount of atleast one active agent in the presence or absence of at least onesecondary agent for the active agents or protective agents for theactive agents. In certain embodiments, the carriers of this inventionare non-aqueous including only residual water and are immiscible inwater or aqueous solutions, but are capable of being dispersed inaqueous solutions releasing the active agent in a pH dependent manner.In other embodiments, the carriers of this invention are oil-basedincluding only residual water and are immiscible in water or aqueoussolutions, but are capable of being dispersed in aqueous solutionsreleasing the active agent.

In certain embodiments, the carriers of this invention may be tailoredto have good targeted active agent release characteristics, to havereduced active agent toxicity or irritation, to have increased activeagent bioavailability, and to have increased active agent migrationacross relatively hydrophobic barriers in a human, mammal or animal.

In other embodiments, the carriers of this invention may be tailored tohave good targeted active agent release characteristics, to have reducedactive agent GI toxicity or irritation, to have increased active agentbioavailability, and to have increased active agent migration acrossrelatively hydrophobic barriers in a human, mammal or animal.

Pharmaceutical and Nutraceutical Compositions

Embodiments of the present invention relates broadly to pharmaceuticalcompositions including a carrier of this invention and an effectiveamount of a pharmaceutical agent or a mixture of pharmaceutical agentsto form a solution and/or a suspension of the pharmaceutical agent orthe mixture of pharmaceutical agents in the carrier. In certainembodiments, the pharmaceutical compositions may be tailored to havegood targeted pharmaceutical release characteristics, to have reducedpharmaceutical toxicity or irritation, to have increased pharmaceuticalbioavailability, and to have increased pharmaceutical migration acrossrelatively hydrophobic barriers in a human, mammal or animal. In otherembodiments, the pharmaceutical compositions may be tailored to havegood targeted pharmaceutical release characteristics, to have reducedpharmaceuticals GI toxicity or irritation, to have increasedpharmaceutical bioavailability, and to have increased pharmaceuticalmigration across relatively hydrophobic barriers in a human, mammal oranimal.

Embodiments of the present invention relates broadly to nutraceuticalcompositions including a carrier of this invention and an effectiveamount of a nutraceutical agent or a mixture of nutraceutical agents toform a solution and/or a suspension of the nutraceutical agent or amixture of nutraceutical agents in the carrier. In certain embodiments,the nutraceutical compositions may be tailored to have good targetednutraceutical release characteristics, to have reduced nutraceuticaltoxicity or irritation, to have increased nutraceutical bioavailability,and to have increased nutraceutical migration across relativelyhydrophobic barriers in a human, mammal or animal. In other embodiments,the nutraceutical compositions may be tailored to have good targetednutraceutical release characteristics, to have reduced nutraceutical GItoxicity or irritation, to have increased nutraceutical bioavailability,and to have increased nutraceutical migration across relativelyhydrophobic barriers in a human, mammal or animal.

In other embodiments, the pharmaceutical agent is an NSAID. In otherembodiments, the NSAID compositions of this invention may also include:(1) a pharmaceutically acceptable amount of antioxidant selected fromthe group consisting of Vitamin A, Vitamin C, Vitamin E or otherantioxidants approved for a human, mammal or animal consumption by theFDA and mixtures or combinations thereof; (2) a pharmaceuticallyacceptable amount of a polyvalent cation selected from the groupconsisting of copper, zinc, gold, aluminum and calcium and mixtures orcombinations thereof; (3) a pharmaceutically acceptable amount of anagent to promote fluidity, enhance viscosity, promote spreadability,promote dispersibility and/or promote permeability selected from thegroup consisting of dimethylsulfoxide (DMSO), propylene glycol (PPG),and medium chain triglyceride/MCT and mixtures or combination thereof;(4) a pharmaceutically acceptable amount of a food coloration ornon-toxic dye; (5) a pharmaceutically acceptable amount of a flavorenhancer; (6) an excipient; and/or (7) an adjuvant.

In other embodiments, the pharmaceutical and/or nutraceutical agent isacid labile. The carriers may be tailored to selectively minimizerelease of the acid labile active agents in the stomach and selectivelytarget release of the acid labile active agent to the small intestinesor the large intestines. This embodiment could be especially useful forpatients at risk for cardiovascular (CV) disease and acid refluxdisease, or an elevated risk of gastrointestinal bleeding that requirethe use of a proton pump inhibitor including but not limited toomemprazole or lansoprazole.

Compositions for Treating

Embodiments of the present invention relates broadly to methodsincluding administering a composition of this invention to a human,mammal or animal. The carriers may be tailored so that the compositionshave good pharmaceutical and/or nutraceutical release characteristics,have reduced pharmaceutical and/or nutraceutical toxicity or irritation,have increased pharmaceutical and/or nutraceutical bioavailability andhave increased pharmaceutical or nutraceutical availability acrossrelatively hydrophobic barriers in a human, mammal or animal. Forexample, pharmaceuticals and/or nutraceuticals that have GI toxicityand/or GI irritation, the carriers of this invention may be tailored toameliorate, reduce or eliminate the GI toxicity and/or GI irritation ofthe pharmaceuticals and/or nutraceuticals. In certain embodiments, thepharmaceutical and/or nutraceutical agents reduce, ameliorate or treatinflammation. In other embodiments, the pharmaceutical and/ornutraceutical agents reduce, ameliorate or treat platelet aggregation.In other embodiments, the pharmaceutical and/or nutraceutical agentsreduce, ameliorate or treat pyretic activity. In other embodiments, thepharmaceutical and/or nutraceutical agents reduce, ameliorate or treatulcerated regions of the tissue. Of course, the pharmaceutical and/ornutraceutical agents reduce, ameliorate or treat combinations of thesesymptoms as well.

Methods for Making the Carriers and Compositions

Embodiments of the present invention relates broadly to methods formaking the carriers of this invention by mixing (1) a biocompatiblefatty acid or a plurality of biocompatible fatty acids, (2) optionally abiocompatible fatty acid ester or a plurality of biocompatible fattyacid esters, (3) optionally a biocompatible oil or a plurality ofbiocompatible oils, (4) optionally a biocompatible fatty acid salt or aplurality of biocompatible fatty acid salts, (5) optionally a secondarycomplexing agent, and (6) optionally a protective system includingagents to reduce and/or eliminate toxicities, irritations orside-effects, under conditions of temperature, pressure and timesufficient to form a carrier having tailored properties. The advantageof the admixing methods is there is not solvent required in preparationand thereby solvent removal.

Embodiments of the present invention also relates broadly to methods formaking the carriers of this invention by mixing, in the presence of asolvent system, (1) a biocompatible fatty acid or a plurality ofbiocompatible fatty acids, (2) optionally a biocompatible fatty acidester or a plurality of biocompatible fatty acid esters, (3) optionallya biocompatible oil or a plurality of biocompatible oils, (4) optionallya biocompatible fatty acid salt or a plurality of biocompatible fattyacid salts, (5) optionally a secondary complexing agent, and (6)optionally a protective system including agents to reduce and/oreliminate toxicities, irritations or side-effects, under conditions oftemperature, pressure and time sufficient to form a carrier havingtailored properties, followed by removal of solvent system. We havedemonstrated that the behavior of the compositions are unaffected by thepreparation with or within solvent.

In certain embodiments, the carriers are generally prepared at roomtemperature, at atmospheric pressure with mixing for a time sufficientto render the carrier uniform and/or homogeneous or substantiallyuniform and/or substantially homogeneous. However, the carrier may beprepare and higher or lower pressures. In other embodiments, the mixingmay be performed at an elevated temperature up to a melting point of thehighest melting component, but below a decomposition temperature of anyof the carrier components. In other embodiments, the temperature iselevated to a temperature up to about 130° C. In other embodiments, thetemperature is elevated to a temperature up to about 80° C. In otherembodiments, the temperature is elevated to a temperature up to about60° C. In other embodiments, the temperature is elevated to atemperature up to about 40° C.

In certain embodiments, the pressure at or near atmospheric pressure. Inother embodiments, the pressure is above atmospheric pressure. In otherembodiments, the pressure is below atmospheric pressure.

In certain embodiments, the time is for a period between about 5 minutesand about 12 hours. In other embodiments, the time is for a periodbetween about 10 minutes and about 8 hours. In other embodiments, thetime is for a period between about 20 minutes and about 4 hours. Inother embodiments, the time is for a period between about 30 minutes andabout 2 hours. In other embodiments, the time is for a period betweenabout 30 minutes and about 1 hour.

In certain embodiments, the mixing is performed by low shear mixing suchas paddle mixers. In other embodiments, the mixing is performed by highshear mixing such as extruders, internal mixers, etc. In certainembodiments, the mixing is performed by a combination of low shearmixing and high shear mixing. In certain embodiments, the mixing isperformed by sonication with or without low shear and/or high shearmixing. In certain embodiments, the mixing is performed by vortex mixingin the presence or absence of sonication.

Embodiments of the present invention relates broadly to methods formaking the compositions of this invention by mixing a carrier of thisinvention and an effective amount of at least one active agent underconditions of temperature, pressure and time sufficient to form acomposition having tailored properties. In certain embodiments, thecompositions may also include a secondary complexing agent for theactive agent under conditions of temperature, pressure and timesufficient to form a composition having tailored properties in thepresence or absence of a solvent system. If solvent system is used, thenthe system is generally removed prior to use. In certain embodiments,the compositions may also include a protective agent for the activeagents. In certain embodiments, the active agents include pharmaceuticalagents, nutraceutical agent or mixtures and combinations thereof. Incertain embodiments, the compositions are made at room temperature, atatmospheric pressure with mixing until the carrier is uniform and/orhomogeneous. In other embodiments, the mixing may be performed at anelevated temperature up to a melting point of the highest meltingcomponent, but below a decomposition temperature of any of the carriercomponents. In other embodiments, the temperature is elevated to atemperature up to about 130° C. In other embodiments, the temperature iselevated to a temperature up to about 80° C. In other embodiments, thetemperature is elevated to a temperature up to about 60° C. In otherembodiments, the temperature is elevated to a temperature up to about40° C. In certain embodiments, the pressure at or near atmosphericpressure. In other embodiments, the pressure is above atmosphericpressure. In other embodiments, the pressure is below atmosphericpressure. In certain embodiments, the time is for a period between about5 minutes and about 12 hours. In other embodiments, the time is for aperiod between about 10 minutes and about 8 hours. In other embodiments,the time is for a period between about 20 minutes and about 4 hours. Inother embodiments, the time is for a period between about 30 minutes andabout 2 hours. In other embodiments, the time is for a period betweenabout 30 minutes and about 1 hour. In certain embodiments, the mixing isperformed by low shear mixing such as paddle mixers. In otherembodiments, the mixing is performed by high shear mixing such asextruders, internal mixers, etc. In certain embodiments, the mixing isperformed by a combination of low shear mixing and high shear mixing. Incertain embodiments, the mixing is performed by sonication with orwithout low shear and/or high shear mixing. In certain embodiments, themixing is performed by vortex mixing in the presence or absence ofsonication. Of course, the compositions may be prepared by mixing theactive agents and the carrier components in any order, thus, the carrierdoes not have to be pre-made prior to adding the active agents.Additionally, the order of addition is not critical and may varydepending on components, mixers, desired final properties, or operatorchoice.

Methods for Using the Carriers and Compositions

Embodiments of the present invention relates broadly to methods forusing the compositions of this invention by administering a compositionof this invention to a human, a mammal or an animal at a dose sufficientto illicit at least one therapeutic effect such as treatment and/orprevention of pain, fever, inflammation, cancer, inflammatory bowelsyndrome, crones disease, cardiovascular disease, infections, brain andspinal cord injury, Alzheimer's disease, other neurologic diseasesdiabetes, and/or any other disease or malady treatable via theadministration of an active agent such as a pharmaceutical and/ornutraceutical agents. In other embodiments, the compositions treat,prevent and/or ameliorate symptoms of diseases and/or maladies.

Embodiments of the present invention relates broadly to methodsincluding orally or internally administering a composition including acarrier of this invention and a therapeutically effective amount of acomposition of this invention to increase transport of thepharmaceutical or nutraceutical agent across the blood-brain barrier orinto the central nervous system (CNS) or peripheral nervous system (PNS)allowing more pharmaceutical or nutraceutical agent to get to the traumasite and reduce inflammation, platelet aggregation, pain (nociceptive)sensation, cell death and/or apoptosis due to inflammation and/orinducing competitive cell death of cancer cells in preventing ortreating cancers.

Embodiments of the present invention relates broadly to methodsincluding orally or internally administering a composition including acarrier of this invention and a therapeutically effective amount of acomposition of this invention to prevent, treat and/or amelioratesymptoms associated with Alzheimer's disease.

Compositional Ranges Used in the Invention Carriers

General Carriers

The carriers of this invention may include:

-   -   (1) 100 wt. % of at least one biocompatible agent,    -   (2) from about 0 wt. % to 100 wt. % of a secondary complexing        agent or a mixture of secondary complexing agents, where the        secondary complexing agents depends on the nature of the active        agent to be carried by the carrier,    -   (3) from about 0 wt. % to about 50 wt. % of a secondary        anti-toxicity agent or a mixture of secondary anti-toxicity        agents, where the secondary anti-toxicity agents depends on the        nature of the active agent to be carried by the carrier, and    -   (4) from about 0 wt. % to about 50 wt. % of (a) an excipient or        a mixture of excipients, (b) an adjuvant or a mixture of        adjuvants, (c) a drying or a mixture of drying agents, (d) a        antioxidant or a mixture of antioxidants, (e) a preservative or        a mixture of preservatives, (f) or a mixture of chelating        agents, (g) a viscomodulator or a mixture of        viscomodulators, (h) a tonicifier or a mixture of        tonicifiers, (I) a flavorant or a mixture of flavorants, (j) a        colorant or a mixture of colorants, (k) a odorant or a mixture        of odorants, (l) a opacifier or a mixture of opacifiers, (m) a        suspending agent or a mixture of suspending agents, and (n)        mixtures thereof.

The carriers of this invention may include:

-   -   (1) 100 wt. % of at least two biocompatible agents,    -   (2) from about 0 wt. % to 100 wt. % of a secondary complexing        agent or a mixture of secondary complexing agents, where the        secondary complexing agents depends on the nature of the active        agent to be carried by the carrier,    -   (3) from about 0 wt. % to about 50 wt. % of a secondary        anti-toxicity agent or a mixture of secondary anti-toxicity        agents, where the secondary anti-toxicity agents depends on the        nature of the active agent to be carried by the carrier, and    -   (4) from about 0 wt. % to about 50 wt. % of (a) an excipient or        a mixture of excipients, (b) an adjuvant or a mixture of        adjuvants, (c) a drying or a mixture of drying agents, (d) a        antioxidant or a mixture of antioxidants, (e) a preservative or        a mixture of preservatives, (f) or a mixture of chelating        agents, (g) a viscomodulator or a mixture of        viscomodulators, (h) a tonicifier or a mixture of        tonicifiers, (I) a flavorant or a mixture of flavorants, (j) a        colorant or a mixture of colorants, (k) a odorant or a mixture        of odorants, (l) a opacifier or a mixture of opacifiers, (m) a        suspending agent or a mixture of suspending agents, and (n)        mixtures thereof.

The above compositions are not formulated to have a total of 100 wt. %of the mixture of the indicated components.

pH Dependent Carriers

The carriers of this invention may include:

-   -   (1) 100 wt. % of at least one pH dependent biocompatible release        agent,    -   (2) from about 0 wt. % to 100 wt. % of a secondary complexing        agent or a mixture of secondary complexing agents, where the        secondary complexing agents depends on the nature of the active        agent to be carried by the carrier,    -   (3) from about 0 wt. % to about 50 wt. % of a secondary        anti-toxicity agent or a mixture of secondary anti-toxicity        agents, where the secondary anti-toxicity agents depends on the        nature of the active agent to be carried by the carrier, and    -   (4) from about 0 wt. % to about 50 wt. % of (a) an excipient or        a mixture of excipients, (b) an adjuvant or a mixture of        adjuvants, (c) a drying or a mixture of drying agents, (d) a        antioxidant or a mixture of antioxidants, (e) a preservative or        a mixture of preservatives, (f) or a mixture of chelating        agents, (g) a viscomodulator or a mixture of        viscomodulators, (h) a tonicifier or a mixture of        tonicifiers, (I) a flavorant or a mixture of flavorants, (j) a        colorant or a mixture of colorants, (k) a odorant or a mixture        of odorants, (l) a opacifier or a mixture of opacifiers, (m) a        suspending agent or a mixture of suspending agents, and (n)        mixtures thereof.

The carriers of this invention may include:

-   -   (1) 100 wt. % of at least one pH dependent biocompatible release        agent,    -   (2) from about 0 wt. % to 100 wt. % of at least one other        biocompatible agent,    -   (3) from about 0 wt. % to 100 wt. % of a secondary complexing        agent or a mixture of secondary complexing agents, where the        secondary complexing agents depends on the nature of the active        agent to be carried by the carrier,    -   (4) from about 0 wt. % to about 50 wt. % of a secondary        anti-toxicity agent or a mixture of secondary anti-toxicity        agents, where the secondary anti-toxicity agents depends on the        nature of the active agent to be carried by the carrier, and    -   (5) from about 0 wt. % to about 50 wt. % of (a) an excipient or        a mixture of excipients, (b) an adjuvant or a mixture of        adjuvants, (c) a drying or a mixture of drying agents, (d) a        antioxidant or a mixture of antioxidants, (e) a preservative or        a mixture of preservatives, (f) or a mixture of chelating        agents, (g) a viscomodulator or a mixture of        viscomodulators, (h) a tonicifier or a mixture of        tonicifiers, (I) a flavorant or a mixture of flavorants, (j) a        colorant or a mixture of colorants, (k) a odorant or a mixture        of odorants, (l) a opacifier or a mixture of opacifiers, (m) a        suspending agent or a mixture of suspending agents, and (n)        mixtures thereof.

The above compositions are not formulated to have a total of 100 wt. %of the mixture of the indicated components.

Fatty Acid pH Dependent Carriers

The carriers of this invention may include:

-   -   (1) from about 0 wt. % to 100 wt. % of a biocompatible fatty        acid or a mixture of biocompatible fatty acids, sometimes        referred to herein as free fatty acids,    -   (2) from about 0 wt. % to 100 wt. % of a biocompatible fatty        acid ester or a mixture of biocompatible fatty acid esters,    -   (3) from about 0 wt. % to 100 wt. % of a biocompatible fatty        acid salt or a mixture of biocompatible fatty acid salts,    -   (4) from about 0 wt. % to 100 wt. % of a biocompatible oil or a        mixture of biocompatible oil,    -   (5) from about 0 wt. % to 100 wt. % of a secondary complexing        agent or a mixture of secondary complexing agents, where the        secondary complexing agents depends on the nature of the active        agent to be carried by the carrier,    -   (6) from about 0 wt. % to about 50 wt. % of a secondary        anti-toxicity agent or a mixture of secondary anti-toxicity        agents, where the secondary anti-toxicity agents depends on the        nature of the active agent to be carried by the carrier, and    -   (7) from about 0 wt. % to about 50 wt. % of (a) an excipient or        a mixture of excipients, (b) an adjuvant or a mixture of        adjuvants, (c) a drying or a mixture of drying agents, (d) a        antioxidant or a mixture of antioxidants, (e) a preservative or        a mixture of preservatives, (f) or a mixture of chelating        agents, (g) a viscomodulator or a mixture of        viscomodulators, (h) a tonicifier or a mixture of        tonicifiers, (I) a flavorant or a mixture of flavorants, (j) a        colorant or a mixture of colorants, (k) a odorant or a mixture        of odorants, (l) a opacifier or a mixture of opacifiers, (m) a        suspending agent or a mixture of suspending agents, and (n)        mixtures thereof.

In other embodiments, the carriers include:

-   -   (1) from about 5 wt. % to 100 wt. % of a biocompatible fatty        acid or a mixture of biocompatible fatty acids, sometimes        referred to herein as free fatty acids,    -   (2) from about 5 wt. % to 100 wt. % of a biocompatible fatty        acid ester or a mixture of biocompatible fatty acid esters,    -   (3) from about 5 wt. % to 100 wt. % of a biocompatible fatty        acid salt or a mixture of biocompatible fatty acid salts,    -   (4) from about 0 wt. % to 100 wt. % of a biocompatible oil or a        mixture of biocompatible oil,    -   (5) from about 0 wt. % to 100 wt. % of a secondary complexing        agent or a mixture of secondary complexing agents, where the        secondary complexing agents depends on the nature of the active        agent to be carried by the carrier,    -   (6) from about 0 wt. % to about 25 wt. % of a secondary        anti-toxicity agent or a mixture of secondary anti-toxicity        agents, where the secondary anti-toxicity agents depends on the        nature of the active agent to be carried by the carrier, and    -   (7) from about 0 wt. % to about 25 wt. % of (a) an excipient or        a mixture of excipients, (b) an adjuvant or a mixture of        adjuvants, (c) a drying or a mixture of drying agents, (d) a        antioxidant or a mixture of antioxidants, (e) a preservative or        a mixture of preservatives, (f) or a mixture of chelating        agents, (g) a viscomodulator or a mixture of        viscomodulators, (h) a tonicifier or a mixture of        tonicifiers, (I) a flavorant or a mixture of flavorants, (j) a        colorant or a mixture of colorants, (k) a odorant or a mixture        of odorants, (l) a opacifier or a mixture of opacifiers, (m) a        suspending agent or a mixture of suspending agents, and (n)        mixtures thereof.

In other embodiments, the carriers include:

-   -   (1) from about 10 wt. % to 100 wt. % of a biocompatible fatty        acid or a mixture of biocompatible fatty acids, sometimes        referred to herein as free fatty acids.    -   (2) from about 10 wt. % to 100 wt. % of a biocompatible fatty        acid ester or a mixture of biocompatible fatty acid esters,    -   (3) from about 10 wt. % to 100 wt. % of a biocompatible fatty        acid salt or a mixture of biocompatible fatty acid salts,    -   (4) from about 0 wt. % to 100 wt. % of a biocompatible oil or a        mixture of biocompatible oil,    -   (5) from about 0 wt. % to 100 wt. % of a secondary complexing        agent or a mixture of secondary complexing agents, where the        secondary complexing agents depends on the nature of the active        agent to be carried by the carrier,    -   (6) from about 0 wt. % to about 25 wt. % of a secondary        anti-toxicity agent or a mixture of secondary anti-toxicity        agents, where the secondary anti-toxicity agents depends on the        nature of the active agent to be carried by the carrier, and    -   (7) from about 0 wt. % to about 25 wt. % of (a) an excipient or        a mixture of excipients, (b) an adjuvant or a mixture of        adjuvants, (c) a drying or a mixture of drying agents, (d) a        antioxidant or a mixture of antioxidants, (e) a preservative or        a mixture of preservatives, (f) or a mixture of chelating        agents, (g) a viscomodulator or a mixture of        viscomodulators, (h) a tonicifier or a mixture of        tonicifiers, (I) a flavorant or a mixture of flavorants, (j) a        colorant or a mixture of colorants, (k) a odorant or a mixture        of odorants, (l) a opacifier or a mixture of opacifiers, (m) a        suspending agent or a mixture of suspending agents, and (n)        mixtures thereof.

The above compositions are formulated to have a total of 100 wt. % of amixtures of the indicated components.

Another way to present the carriers is in weight ratios of components.In certain embodiments, the ratio of ingredient classes is 1-3:4:5:6:7is from 1:0:0:0:0 to 0:1:0:0:0 to 1:0:1:1:1 to 0:1:1:1:1. In otherembodiments, the ratio of ingredient classes is 1-3:4:5:6:7 is from10:1:0:0:0 to 1:10:0:0:0 to 10:1:1:1:1:1 to 1:10:1:1:1. In otherembodiments, the ratio of ingredient classes is 1-3:4:5:6:7 is from5:1:0:0:0 to 1:5:0:0:0 to 5:1:1:1:1:1 to 1:5:1:1:1. In otherembodiments, the ratio of ingredient classes is 1-3:4:5:6:7 is from4:1:0:0:0 to 1:4:0:0:0 to 4:1:1:1:1:1 to 1:4:1:1:1. In otherembodiments, the ratio of ingredient classes is 1-3:4:5:6:7 is from3:1:0:0:0 to 1:3:0:0:0 to 3:1:1:1:1:1 to 1:3:1:1:1. In otherembodiments, the ratio of ingredient classes is 1-3:4:5:6:7 is from2:1:0:0:0 to 1:2:0:0:0 to 2:1:1:1:1:1 to 1:2:1:1:1. In otherembodiments, the ratio of ingredient classes is 1-3:4:5:6:7 is from1:1:0:0:0 to 1:1:1:1:1:1. Of course, the actual value of each level mayrange through the entire range within the individual ranges.

The carrier and/or the carrier components are designed to modify and/oralter the chemical and/or physical properties and/or behavior of atleast one active agent in tissues and/or organs reducing and/or alteringtissue and/or organ toxicity, improving and/or altering bioavailability,and/or improving and/or altering efficacy. In certain embodiments, thecarriers and/or the biocompatible, hydrophobic agents modify and/oralter the chemical and/or physical properties and/or behavior of atleast one active agent in tissues and/or organs in a pH dependent mannerto reduce and/or alter tissue and/or organ toxicity, improve and/oralter bioavailability, and/or improve and/or alter efficacy.

In certain embodiments, the carrier comprises between about 100 wt. %and 50 wt. % biocompatible oils and between about 0 wt. % and 50 wt. %biocompatible fatty acids. In other embodiments, between about 0 wt. %and 50 wt. % biocompatible oils and between about 100 wt. % and 50 wt. %biocompatible fatty acids.

Low Phospholipid Carriers

In certain embodiments, the carrier comprises between about 100 wt. %and 99 wt. % biocompatible oils and between about 0 wt. % and 1 wt. %phospholipids. In other embodiments, between about 100 wt. % and 98 wt.% biocompatible oils and between about 0 wt. % and 2 wt. %phospholipids. In other embodiments, between about 100 wt. % and 95 wt.% biocompatible oils and between about 0 wt. % and 5 wt. %phospholipids. In other embodiments, between about 100 wt. % and 90 wt.% biocompatible oils and between about 0 wt. % and 10 wt. %phospholipids.

In other embodiments, the carrier comprises between about 100 wt. % and80 wt. % biocompatible oils, between about 0 wt. % and about and betweenabout 10 wt. % biocompatible fatty acids, and between about 0 wt. % and10 wt. % phospholipids. In other embodiments, the carrier comprisesbetween about 100 wt. % and 40 wt. % biocompatible oils, between about 0wt. % and about and between about 40 wt. % biocompatible fatty acids,and between about 0 wt. % and 10 wt. % phospholipids.

In certain embodiments, the carrier comprises between about 100 wt. %and 80 wt. % biocompatible fatty acids, between about 0 wt. % and aboutand between about 10 wt. % biocompatible oils, and between about 0 wt. %and 10 wt. % phospholipids. In other embodiments, between about 100 wt.% and 40 wt. % biocompatible fatty acids, between about 0 wt. % andabout and between about 40 wt. % biocompatible oils, and between about 0wt. % and 10 wt. % phospholipids.

In certain embodiments, the carrier may also include between about 0.5wt. % and about 2 wt. % sterols, between about 5 wt. % and about 10 wt.% glycolipids, and between about 0.5 wt. % and 2 wt. %, less than 2 wt.% water. The phospholipids comprise between about 75 wt. % and about 100wt. % phosphatidylcholine, between about 0 wt. % and about 10 wt. %phophatidylethanolmine, between about lyso-phosphatidylcholine 0 wt. %and about 10 wt. %, and between about 0 wt. % and about 2 wt. %monophosphotidylinositol. The biocompatible oils comprises between about50 wt. % and 80 wt. % triglycerides, between about 0 wt. % and 5 wt. %mono & diglycerides, between about 5 wt. % and about 20 wt. % free fattyacids.

High Phospholipid Carriers

In certain embodiments, the carrier comprises between about 30 wt. % and50 wt. % phospholipids, between about 30 wt. % and 50 wt. %biocompatible oils, between about 0.5 wt. % and about 2 wt. % sterols,between about 5 wt. % and about 10 wt. % glycolipids, and between about0.5 wt. % and 2 wt. %, less than 2 wt. % water. The phospholipidscomprise between about 75 wt. % and about 100 wt. % phosphatidylcholine,between about 0 wt. % and about 10 wt. % phophatidylethanolmine, betweenabout lyso-phosphatidylcholine 0 wt. % and about 10 wt. %, and betweenabout 0 wt. % and about 2 wt. % monophosphotidylinositol. Thebiocompatible oils comprises between about 50 wt. % and 80 wt. %triglycerides, between about 0 wt. % and 5 wt. % mono & diglycerides,between about 5 wt. % and about 20 wt. % free fatty acids.

In certain embodiments, the carrier comprises between about 30 wt. % and50 wt. % phospholipids, between about 30 wt. % and 50 wt. %biocompatible oils, between about 0.5 wt. % and about 2 wt. % sterols,between about 5 wt. % and about 10 wt. % glycolipids, and between about0.5 wt. % and 2 wt. %, less than 2 wt. % water. The phospholipidscomprise between about 75 wt. % and about 100 wt. % phosphatidylcholine,between about 0.1 wt. % and about 10 wt. % phophatidylethanolmine,between about lyso-phosphatidylcholine 0.1 wt. % and about 10 wt. %, andbetween about 0.5 wt. % and about 2 wt. % monophosphotidylinositol. Thebiocompatible oils comprises between about 50 wt. % and 80 wt. %triglycerides, between about 0.5 wt. % and 5 wt. % mono & diglycerides,between about 5 wt. % and about 20 wt. % free fatty acids.

Free Fatty Acid, Biocompatible Oil, and Phospholipid Compositions

In certain embodiments, the carriers comprise free fatty acids (FFAs),biocompatible oils (BCOs), and phospholipids (PLs) in a weight ratio ofa:b:c (FFAs:BCOs:PLs), where a ranges from 1 to 10, b ranges from 0 to10, and c ranges from 0 to 10. In certain embodiments, a ranges from 0to 10, b ranges from 1 to 10, and c ranges from 0 to 10. In certainembodiments, a ranges from 1 to 10, b ranges from 1 to 10, and c rangesfrom 0 to 10. The FFAs in the carriers may be a single free fatty acidor a mixture of free fatty acids as defined herein. The BCOs in thecarriers may be a single biocompatible oil or a mixture of biocompatibleoils. The PLs in the carriers may be a single phospholipid or a mixtureof phospholipids.

In certain embodiments, the carriers comprise free fatty acids (FFAs),neutral lipids (NLs), and phospholipids (PLs) in weight ratios a:b:c(FFAs:NLs:PLs), where a ranges from 1 to 10, b ranges from 0 to 10, andc ranges from 0 to 10. In certain embodiments, a ranges from 0 to 10, branges from 1 to 10, and c ranges from 0 to 10. In certain embodiments,a ranges from 1 to 10, b ranges from 1 to 10, and c ranges from 0 to 10.The FFAs in the carriers may be a single free fatty acid or a mixture offree fatty acids as defined herein. The NLs in the carriers may be asingle neutral lipid or a mixture of neutral lipids, where the neutrallipids comprise mono-, di- and/or tri-glycerides. The PIs in thecarriers may be a single phospholipid or a mixture of phospholipids.

Secondary Complexing Agent and/or Anti-Toxicity Agents

NSAIDs

In certain NSAID compositions, the secondary anti-toxicity agentsinclude less than or equal to about 10 wt. % of at least onezwitterionic agent such as a zwitterionic surfactant. In other NSAIDcompositions, the secondary anti-toxicity agents include less than orequal to about 7.5 wt. % of at least one zwitterionic agent such as azwitterionic surfactant. In other NSAID compositions, the secondaryanti-toxicity agents include less than or equal to about 5 wt. % of atleast one zwitterionic agent such as zwitterionic surfactants. In otherNSAID compositions, the secondary anti-toxicity agents include less thanor equal to about 2.5 wt. % of at least one zwitterionic agent such aszwitterionic surfactants. In other NSAID compositions, the secondaryanti-toxicity agents include from about 0.1 wt. % to about 10 wt. % ofat least one zwitterionic agent such as zwitterionic surfactants. Inother NSAID compositions, the secondary anti-toxicity agents includefrom about 0.5 wt. % to about 10 wt. % of at least one zwitterionicagent such as zwitterionic surfactants. In other NSAID compositions, thesecondary anti-toxicity agents include from about 1 wt. % to about 10wt. % of at least one zwitterionic agent such as zwitterionicsurfactants. In other NSAID compositions, the secondary anti-toxicityagents include from about 2 wt. % to about 10 wt. % of at least onezwitterionic agent such as zwitterionic surfactants.

In certain NSAID compositions, the secondary anti-toxicity agentsinclude from about 0 wt. % to about 50 wt. % of at least onetriglyceride neutral lipid. In other NSAID compositions, the secondaryanti-toxicity agents include from about 0.1 wt % to about 10 wt. % of atleast one proton pump inhibitor (PPI).

In certain NSAID compositions, the secondary anti-toxicity agentsinclude less than or equal to about 10 wt. % of at least onezwitterionic agent and from about 0 wt. % to about 50 wt. % of at leastone neutral lipid. In other NSAID compositions, the secondaryanti-toxicity agents include less than or equal to about 10 wt. % of atleast one zwitterionic agent and from about 1 wt. % to about 50 wt. % ofat least one neutral lipid.

In certain NSAID compositions, the secondary anti-toxicity agentsinclude less than or equal to about 10 wt. % of at least onezwitterionic agent and from about 0 wt. % to about 10 wt. % of at leastone PPI. In other NSAID compositions, the secondary anti-toxicity agentsinclude less than or equal to about 10 wt. % of at least onezwitterionic agent and from about 0.5 wt. % to about 10 wt. % of atleast one PPI. In other NSAID compositions, the secondary anti-toxicityagents include less than or equal to about 10 wt. % of at least onezwitterionic agent, from about 0.5 wt. % to about 50 wt. % of at leastone neutral lipid, and from about 0.5 wt. % to about 10 wt. % of atleast one PPI.

Compositions

The compositions of this invention may generally be formulated with atleast one biologically active agent as a major component.

The compositions of this invention may have weight ratios of activeagents to carrier, where the carrier is present in an amount of form atleast a monolayer coating on the active agents. In certain embodiment,the weight ratios of active agents to carrier is from about 100:1 toabout 1:100. In other embodiment, the ratio is between about 100:1 andabout 1:10. In other embodiment, the ratio is between about 50:1 andabout 1:5. In other embodiment, the ratio is between about 25:1 andabout 1:5. In other embodiment, the ratio is between about 10:1 andabout 1:1. In other embodiments, the ratio is between about 5:1 andabout 1:1. In other embodiments, the ratio is from about 5:1 to about1:1. The term about means±5%.

Pharmaceutical or Nutraceutical Dosages

In pharmaceutical compositions, the compositions will generally containfrom about 1 mg to about 5000 mg per dose depending on thepharmaceutical agent(s). In other pharmaceutical compositions, thecompositions will contain from about 10 mg to about 2500 mg per dosedepending on the pharmaceutical agent(s). In other pharmaceuticalcompositions, the compositions will contain from about 250 mg to about2500 mg per dose depending on the pharmaceutical agent(s). In otherpharmaceutical compositions, the compositions will contain from about500 mg to about 2500 mg per dose depending on the pharmaceuticalagent(s). In other pharmaceutical compositions, the compositions willcontain from about 500 mg to about 2000 mg per dose depending on thepharmaceutical agent(s). In other pharmaceutical compositions, thecompositions will contain from about 1 mg to about 2000 mg per dosedepending on the pharmaceutical agent(s). In other pharmaceuticalcompositions, the compositions will contain from about 1 mg to about1000 mg per dose depending on the pharmaceutical agent(s). Of course,the exact dosage for each compositions will depend on the pharmaceuticalagent(s) used and the potency of the pharmaceutical agent(s).

In nutraceutical compositions, the compositions will generally containfrom about 1 mg to about 5000 mg per dose depending on the nutraceuticalagent(s). In other nutraceutical compositions, the compositions willcontain from about 10 mg to about 2500 mg per dose depending on thenutraceutical agent(s). In other nutraceutical compositions, thecompositions will contain from about 250 mg to about 2500 mg per dosedepending on the nutraceutical agent(s). In other nutraceuticalcompositions, the compositions will contain from about 500 mg to about2500 mg per dose depending on the nutraceutical agent(s). In othernutraceutical compositions, the compositions will contain from about 500mg to about 2000 mg per dose depending on the nutraceutical agent(s). Inother nutraceutical compositions, the compositions will contain fromabout 1 mg to about 2000 mg per dose depending on the nutraceuticalagent(s). In other nutraceutical compositions, the compositions willcontain from about 1 mg to about 1000 mg per dose depending on thenutraceutical agent(s). Of course, the exact dosage for eachcompositions will depend on the pharmaceutical agent(s) used and thepotency of the pharmaceutical agent(s).

Reagents Suitable for Use in the Invention pH Dependent Release Agents

Fatty Acids

Suitable biocompatible fatty acids for use in this invention include,without limitation, any saturated fatty acid or unsaturated fatty acidsor mixtures or combinations thereof suitable for a human, mammal oranimal consumption. Exemplary fatty acids include short chain free fattyacids (SCFFA), medium chain free fatty acids (MCFFA), long chain freefatty acids (LCFFA), very-long-chain free fatty acids (VLCFFA) andmixtures or combinations thereof. SCFFA include free fatty acids havinga carbyl tail group having less than between 4 and less than 8 carbonatoms (C₄ to C₈). MCFFA include free fatty acids having a carbyl grouphaving between 8 and less than 14 carbon atoms (C₈ to C₁₄). LCFFAinclude free fatty acids having a carbyl group having between 14 and 24carbon atoms (C₁₄-C₂₄). VLCFFA include free fatty acids having a carbylgroup having greater than 24 carbon atoms (>C₂₄). Exemplary unsaturatedfatty acids include, without limitation, myristoleic acid[CH₃(CH₂)₃CH═CH(CH₂)₇COOH, cis-Δ⁹, C:D 14:1, n-5], palmitoleic acid[CH₃(CH₂)₅CH═CH(CH₂)₇COOH, cis-Δ⁹, C:D 16:1, n-7], sapienic acid[CH₃(CH₂)₈CH═CH(CH₂)₄COOH, cis-Δ⁶, C:D 16:1, n-10], oleic acid[CH₃(CH₂)₇CH═CH(CH₂)₇COOH, cis-Δ⁹, C:D 18:1, n-9], linoleic acid[CH₃(CH₂)₄CH═CHCH₂CH═CH(CH₂)₇COOH, cis,cis-Δ⁹,Δ¹², C:D 18:2, n-6],α-Linolenic acid [CH₃CH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₇COOH,cis,cis,cis-Δ⁹,Δ¹²,Δ¹⁵, C:D 18:3, n-3], arachidonic acid[CH₃(CH₂)₄CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₃COOH,cis,cis,cis,cis-Δ⁵,Δ⁸,Δ¹¹,Δ¹⁴, C:D 20:4, n-6], eicosapentaenoic acid[CH₃CH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₃COOH],cis,cis,cis,cis,cis-Δ⁵,Δ⁸,Δ¹¹,Δ¹⁴,Δ¹⁷, 20:5, n-3], erucic acid[CH₃(CH₂)₇CH═CH(CH₂)₁₁COOH, cis-Δ¹³, C:D 22:1, n-9], docosahexaenoicacid [CH₃CH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₂COOH,cis,cis,cis,cis,cis,cis-Δ⁴,Δ⁷,Δ¹⁰,Δ¹³,Δ¹⁶,Δ¹⁹, C:D 22:6, n-3], ormixtures and combinations thereof.

Exemplary saturated fatty acids include, without limitation, lauric acid[CH₃(CH₂)₁₀COOH, C:D 12:0], myristic acid [CH₃(CH₂)₁₂COOH, C:D 14:0],palmitic acid [CH₃(CH₂)₁₄COOH, C:D 16:0], stearic acid [CH₃(CH₂)₁₆COOH,C:D 18:0], arachidic acid [CH₃(CH₂)₁₈COOH, C:D 20:0], behenic acid[CH₃(CH₂)₂₀COOH, C:D 22:0], lignoceric acid [H₃(CH₂)₂₂COOH, C:D 24:0],cerotic acid [CH₃(CH₂)₂₄COOH, C:D 26:0], or mixture or combinationsthereof.

Exemplary saturated fatty acids include, without limitation, butyric(C₄), valeric (C₅), caproic (C₆), enanthic (C₇), caprylic (C₈),pelargonic (C₉), capric (C₁₀), undecylic (C₁₁), lauric (C₁₂), tridecylic(C₁₃), myristic (C₁₄), pentadecylic (C₁₅), palmitic (C₁₆), margaric(C₁₇), stearic (C₁₈), nonadecylic (C₁₉), arachidic (C₂₀), heneicosylic(C₂₁), behenic (C₂₂), tricosylic (C₂₃), lignoceric (C₂₄), pentacosylic(C₂₅), cerotic (C₂₆), heptacosylic (C₂₇), montanic (C₂₈), nonacosylic(C₂₉), melissic (C₃₀), hentriacontylic (C₃₁), lacceroic (C₃₂), psyllic(C₃₃), geddic (C₃₄), ceroplastic (C₃₅), hexatriacontylic (C₃₆) andmixtures or combinations thereof. Unsaturated fatty acids include,without limitation, n-3 unsaturated fatty acids such as α-linolenicacid, stearidonic acid, eicosapentaenoic acid, and docosahexaenoic acid,n-6 unsaturated fatty acids such as linoleic acid, γ-linolenic acid,dihomo-γ-linolenic acid, and arachidonic acid, n-9 unsaturated fattyacids oleic acid, elaidic acid, eicosenoic acid, erucic acid, nervonicacid, mead acid and mixtures or combinations thereof.

Poly Acids

Suitable poly carboxylic acid compounds for use a pH depending releaseagents include, without limitation, any poly carboxylic acid compound.Exemplary examples of water immiscible poly acids include, withoutlimitation, dicarboxylic acids having carbyl or carbenyl groups havingbetween 8 and 50 carbon atoms and mixtures or combinations thereof.Polymer carboxylic acids or polymers including carboxylic acid groups,where the polymers are oil soluble or are oils, not miscible with water.Exemplary example of hydrophilic poly acids include, without limitation,polyacrylic acid, polymethacrylic acid, polylactic acid, polyglycolacid, mixtures and combinations thereof, copolymers thereof, CARBOPOL®reagents available from Lubrizol Corporation (a registered trademark ofthe Lubrizol Corporation), other carboxylic acid containing polymers, ormixtures or combinations thereof.

Fatty Acid Esters

Fatty acid esters comprise esters of any of the fatty acids listed aboveincluding, without limitation, mono-alcohol esters, where themono-alcohol or polyols including 1 carbon atom to 20 carbon atoms,where one or more of the carbon atoms may be replace by O, NR (R is acarbyl group having between 1 and 5 carbon atoms), or S. Exemplarymono-alcohols used to from the free fatty acid esters include methanol,ethanol, propanol, butanol, pentanol or mixtures thereof.

Fatty Acid Salts

Suitable biocompatible fatty acid salts for use in this inventioninclude, without limitation, alkali metal salts of any of the abovelisted fatty acids, alkaline earth metals salts of any of the abovelisted fatty acids, transition metal salts of any of the above listedfatty acids or mixture or combinations thereof. In certain embodiments,the metal salts include lithium, sodium, potassium, cesium, magnesium,calcium, barium, copper, zinc, cobalt, iron, or mixture or combinationsthereof.

Secondary Complexing Agents and/or Anti-Toxicity Agents

Suitable secondary complexing agents and/or secondary anti-toxicityagents for use in the compositions of this invention include, withoutlimitation, phospholipids, amphoteric agents and/or zwitterionic agentsor mixtures or combinations thereof. Phospholipids include anyphospholipid or mixtures and combinations thereof such as (1)diacylglyceride phospholipids or glycerophospholipids include, withoutlimitation, phosphatidic acid (phosphatidate) (PA),phosphatidylethanolamine (cephalin) (PE), phosphatidylcholine (lecithin)(PC), phosphatidylserine (PS), phosphoinositides such asphosphatidylinositol (PI), phosphatidylinositol phosphate (PIP),phosphatidylinositol bisphosphate (PIP2) and phosphatidylinositoltriphosphate (PIP3), and (2) phosphosphingolipids such as ceramidephosphorylcholine (Sphingomyelin) (SPH), ceramide phosphorylethanolamine(Sphingomyelin) (Cer-PE), and ceramide phosphorylglycerol. Amphotericagents include acetates, betaines, glycinates, imidazolines,propionates, other amphoteric agents or mixtures thereof. Zwitterionicagents include, without limitation, biocompatible, zwitterionicphospholipids, biocompatible, zwitterionic betaines, biocompatible,biocompatible amphoteric/zwitterionic surfactants, biocompatiblequaternary salts, biocompatible amino acids, other biocompatiblecompounds capable of forming or in the form of a zwitterion, or mixturesor combinations thereof.

Suitable biocompatible, zwitterionic phospholipids for use in thisinvention include, without limitation, a phospholipid of generalformula:

where R¹ and R² are saturated or unsaturated substitutions ranging from8 to 32 carbon atoms; R³ is H or CH₃, and X is H or COOH; and R⁴ is ═Oor H₂. Mixtures and combinations of the zwitterionic phospholipids ofthe general formula and mixtures and combinations of NSAIDs can be usedas well.

Exemplary examples of zwitterionic phospholipid of the above formulainclude, without limitation, phosphatidylcholines such as phosphatidylcholine (PC), dipalmitoylphosphatidylcholine (DPPC), other disaturatedphosphatidylcholines, phosphatidylethanolamines, phosphatidylinositol,phosphatidylserines sphingomyelin or other ceramides, or various otherzwitterionic phospholipids, phospholipid containing oils such aslecithin oils derived from soy beans, dimyristoylphosphatidylcholine,distearoylphosphatidylcholine, dilinoleoylphosphatidylcholine (DLL-PC),dipalmitoylphosphatidylcholine (DPPC), soy phophatidylchloine (Soy-PC orPC_(S)) and egg phosphatidycholine (Egg-PC or PC_(E)). In DPPC, asaturated phospholipid, the saturated aliphatic substitution R₁ and R₂are CH₃—(CH₂)₁₄, R₃ is CH₃ and X is H. In DLL-PC, an unsaturatedphospholipid, R₁ and R₂ are CH₃—(CH₂)₄—CH══CH—CH₂—CH══CH—(CH₂)₇, R₃ isCH₃ and X is H. In Egg PC, which is a mixture of unsaturatedphospholipids, R₁ primarily contains a saturated aliphatic substitution(e.g., palmitic or stearic acid), and R₂ is primarily an unsaturatedaliphatic substitution (e.g., oleic or arachidonic acid). In Soy-PC,which in addition to the saturated phospholipids (palmitic acid andstearic acid) is a mixture of unsaturated phospholipids (oleic acid,linoleic acid and linolenic acid). In certain embodiments, thephospholipids are zwitterionic phospholipid include, without limitation,dipalmitoyl phosphatidylcholine, phosphatidyl choline, or a mixturethereof.

Exemplary acetates include, without limitation, lauroamphoacetate, alkylamphoacetate, cocoampho(di)acetae, cocoamphoacetate, cocoamphodiacetate,disodium cocoamphodiacetate, sodium cocoamphoacetate, sodiumlauroamphoacetate, disodium cocoamphodiacetate, disodiumcapryloamphodiacetate, disodium lauroamphoacetate, disodiumwheatgermamphodiacetate, cocoamphoacetate, cocoamphoacetate,cocoamphoacetate, cocoamphoacetate and cocoamphodiacetate, disodiumcocoamphodiacetate, and mixtures or combinations thereof.

Exemplary betaines include, without limitation, cocamidopropyl betaine,sodium lauroamphoace, cocoamidopropyl hydroxy sulfo baden (CHSB),dodecyl dimethyl betaine, cetyl betaine, lauroamphoacetate, alkylamphoacetate, cocoampho(di)acetate, cocoamphoacetate,cocoamphodiacetate, disodium cocoamphodiacetate, sodiumcocoamphoacetate, sodium lauroamphoacetate, disodium cocoamphodiacetate,disodium capryloamphodiacetate, disodium lauroamphoacetate, disodiumwheatgermamphodiacetate, cocoamphoacetate, alkylamido baden;alkyldimethyl betaine, cocoamidopropylbetaine, tallowbis(hydroxyethyl)baden, hexadecyldimethylbetaine, alkyl amido propylsulfo baden, alkyl dimethyl amine baden, coco amido propyl dimethylbaden, alkyl amido propyl dimethyl amine baden, cocamidopropyl baden,lauryl betaine, laurylamidopropyl betaine, coco amido baden, laurylamido baden, dimethicone propyl PG-betaine, N-alkyldimethyl betaine,coco biguamide derivative, cetyl baden, oleamidopropyl betaine,isostearamidopropyl betaine, oleyl betaine, wheatgermamidopropylbetaine, cocamidopropyl betaine, lauramidopropyl betaine,2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium baden;cocamidopropyl betaine, isostearamidopropyl betaine, myristamidopropylbetaine, palmitamidopropyl betaine, cocamidopropyl hydroxy sultaine,ammonium chloride cocamidopropyl hydroxy sultaine and potassiumchloride, cocamidopropyl hydroxy sultaine, undecylenamidopropyl baden,wheatgermamidopropyl betaine, or mixture and combinations thereof.

Exemplary glycinates including, without limitation, Ampholak 7CX,Ampholak X07, cocoamphocarboxyglycinate, tallowamphocarboxyglycinate,oleoamphocarboxyglycinate, cocoiminodiglycinate,capryloamphocarboxyglycinate, bis-2-hydroxyethyl tallow glycinate,lauryl amphoglycinate, oleic polyamphoglycinate, —C_(10/12)-fatty acidamidoethyl-N-(2-hydroxyethyl)-glycinate, —C_(12/18)-fatty acidamidoethyl-N-(2-hydroxyethyl)-glycinate, dihydroxyethyl tallowglycinate, and mixtures or combinations thereof.

Exemplary imidazolines including, without limitation,2-alkyl-1-(ethyl-beta-oxipropanoianoic)imidazoline sodium salt based oncaprylic acid, 1-hydroxyethyl-2-alkylimidazoline, coco imidazoline, talloil imidazoline, lauryl imidazoline, coco imidazolinedicarboxymethylated, sodium copra dicarboxylic imidazoline, oleylimidazoline and mixtures or combinations thereof.

Exemplary propionates including, without limitation,cocoiminodipropionate, octyliminodipropionate, cocoalkylaminopropionicacid, cocoamphodipropionate, lauraminopropionic acid,disodium-tallow-P-iminodipropionate, monosodium-N-laurylP-iminodipropionic acid, disodium lauriminodipropionate, sodiumlauriminopropionic acid, 2-ethylhexylamino dipropionate, coco aminodipropionate, cocaminopropionic acid, lauraminopropionic acid, sodiumlauriminodipropionate, disodium cocoamphodipropionate, disodiumcapryloamphodipropionate, disodium lauroamphodipropionate, sodiumcocoamphopropionate, sodium lauriminodipropionate, sodiumalkyliminopropionate and mixtures or combinations thereof.

Exemplary other amphoteric agents including, without limitation,N-coco-3-aminobutyric acid, sodium salt, N-coco-3-aminobutyric acid,ethoxylated fatty alcohol carboxym, cocamidopropyl hydroxy sultaine,sodium cocoamphohydroxypropyl sulfonate, sodiumcapryloarnphohydroxypropyl sulfonate and mixtures or combinationsthereof.

Pharmaceutical Agents

Suitable pharmaceutical agents for use in the compositions of thisinvention include, without limitation, any pharmaceutical agent capableof being dispersed in a carrier of this invention. In certainembodiments, the pharmaceutical agents are solids. In other embodiments,the pharmaceutical agents are liquids. In other embodiments, thepharmaceutical agents are weak acid pharmaceutical agents. In otherembodiments, the pharmaceutical agents are weak base pharmaceuticalagents.

Hydrophobic Pharmaceutical and/or Nutraceutical Agents

Hydrophobic therapeutic agents suitable for use in the pharmaceuticalcompositions of the present invention are not particularly limited, asthe carrier is surprisingly capable of solubilizing and delivering awide variety of hydrophobic therapeutic agents. Hydrophobic therapeuticagents are compounds with little or no water solubility. Intrinsic watersolubilities (i.e., water solubility of the unionized form) forhydrophobic therapeutic agents usable in the present invention are lessthan about 1% by weight, and typically less than about 0.1% or 0.01% byweight. Such therapeutic agents can be any agents having therapeutic orother value when administered to an animal, particularly to a mammal,such as drugs, nutrients, and cosmetics (cosmeceuticals). It should beunderstood that while the invention is described with particularreference to its value in the form of aqueous dispersions, the inventionis not so limited. Thus, hydrophobic drugs, nutrients or cosmetics whichderive their therapeutic or other value from, for example, topical ortransdermal administration, are still considered to be suitable for usein the present invention.

Specific non-limiting examples of hydrophobic therapeutic agents thatcan be used in the pharmaceutical compositions of the present inventioninclude the following representative compounds, as well as theirpharmaceutically acceptable salts, isomers, esters, ethers and otherderivatives: analgesics and anti-inflammatory agents, such as aloxiprin,auranofin, azapropazone, benorylate, capsaicin, celecoxib, diclofenac,diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen,ibuprofen, indomethacin, ketoprofen, ketorolac, leflunomide,meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin,oxyphenbutazone, phenylbutazone, piroxicam, refocoxib, sulindac,tetrahydrocannabinol, tramadol and tromethamine: antihelminthics, suchas albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen,ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel embonate,praziquantel, pyrantel embonate and thiabendazole; anti-arrhythmicagents, such as amiodarone HCl, disopyramide, flecainide acetate andquinidine sulfate; anti-asthma agents, such as zileuton, zafirlukast,terbutaline sulfate, montelukast, and albuterol: anti-bacterial agentssuch as alatrofloxacin, azithromycin, baclofen, benzathine penicillin,cinoxacin, ciprofloxacin HCl, clarithromycin, clofazimine, cloxacillin,demeclocycline, dirithromycin, doxycycline, erythromycin, ethionamide,furazolidone, grepafloxacin, imipenem, levofloxacin, lorefloxacin,moxifloxacin HCl, nalidixic acid, nitrofurantoin, nortloxacin,ofloxacin, rifampicin, rifabutine, rifapentine, sparfloxacin,spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine,sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole,sulphapyridine, tetracycline, trimethoprim, trovafloxacin, andvancomycin; anti-viral agents, such as abacavir, amprenavir,delavirdine, efavirenz, indinavir, lamivudine, nelfinavir, nevirapine,ritonavir, saquinavir, and stavudine; anti-coagulants, such ascilostazol, clopidogrel, dicumarol, dipyridamole, nicoumalone,oprelvekin, phenindione, ticlopidine, and tirofiban; anti-depressants,such as amoxapine, bupropion, citalopram, clomipramine, fluoxetine HCl,maprotiline HCl, mianserin HCl, nortriptyline HCl, paroxetine HCl,sertraline HCl, trazodone HCl, trimipramine maleate, and venlafaxineHCl; anti-diabetics, such as acetohexamide, chlorpropamide,glibenclamide, gliclazide, glipizide, glimepiride, miglitol,pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide andtroglitazone; anti-epileptics, such as beclamide, carbamazepine,clonazepamn, ethotoin, felbamate, fosphenytoin sodium, lamotrigine,methoin, methsuximide, methylphenobarbitone, oxcarbazepine,paramethadione, phenacemide, phenobarbitone, phenytoin, phensuximide,primidone, sulthiame, tiagabine HCl, topiramate, valproic acid, andvigabatrin; anti-fungal agents, such as amphotericin, butenafine HCl,butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole,flucytosine, griscofulvin, itraconazole, ketoconazole, miconazole,natamycin, nystatin, sulconazole nitrate, oxiconazole, terbinafine HCl,terconazole, tioconazole and undecenoic acid; anti-gout agents, such asallopurinol, probenecid and sulphin-pyrazone: anti-hypertensive agents,such as amlodipine, benidipine, benezepril, candesartan, captopril,darodipine, dilitazem HCl, diazoxide, doxazosin HCl, elanapril,eposartan, losartan mesylate, felodipine, fenoldopam, fosenopril,guanabenz acetate, irbesartan, isradipine, lisinopril, minoxidil,nicardipine HCl, nifedipine, nimodipine, nisoldipine, phenoxybenzamineHCl, prazosin HCl, quinapril, reserpine, terazosin HCl, telmisartan, andvalsartan; anti-malarials, such as amodiaquine, chloroquine,chlorproguanil HCl, halofantrine HCl, mefloquine HCl, proguanil HCl,pyrimethamine and quinine sulfate; anti-migraine agents, such asdihydroergotamine mesylate, ergotamine tartrate, frovatriptan,methysergide maleate, naratriptan HCl, pizotyline malate, rizatriptanbenzoate, sumatriptan succinate, and zolmitriptan; anti-muscarinicagents, such as atropine, benzhexol HCl, biperiden, ethopropazine HCl,hyoscyamine, mepenzolate bromide, oxyphencyclimine HCl and tropicamnide;anti-neoplastic agents and immunosuppressants, such asaminoglutethimide, amsacrine, azathioprine, bicalutamide, bisantrene,busulfan, camptothecin, cytarabine, chlorambucil, cyclosporin,dacarbazine, ellipticine, estramustine, etoposide, irinotecan,lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane,mitoxantrone, mofetil mycophenolate, nilutamide, paclitaxel,procarbazine HCl, sirolimus, tacrolimnus, tamoxifen citrate, teniposide,testolactone, topotecan HCl, and toremifene citrate: anti-protozoalagents, such as atovaquone, benznidazole, clioquinol, decoquinate,diiodohydroxyquinoline, diloxanide furoate, dinitolmide, furazolidone,metronidazole, nimorazole, nitrofurazone, ornidazole and tinidazole;anti-thyroid agents, such as carbimazole, paracalcitol, andpropylthiouracil; anti-tussives, such as benzonatate; anxiolytics,sedatives, hypnotics and neuroleptics, such as alprazolam,amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol,brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlormethiazole,chlorpromazine, chlorprothixene, clonazepam, clobazam, clotiazepam,clozapine, diazepam, droperidol, ethinamate, flunanisone, flunitrazepam,triflupromazine, fluphenthixol decanoate, fluphenazine decanoate,fiurazepam, gabapentin, haloperidol, lorazepam, lormetazepam, medazepam,meprobamate, mesoridazine, methaqualone, methylphenidate, midazolam,molindonec nitrazepam, olanzapine, oxazepam, pentobarbitone,perphenazine pimozide, prochlorperazine, pseudoephedrine, quetiapine,rispiridone, sertindole, sulpiride, teniazepam, thioridazine, triazolam,zolpidem, and zopiclone; .beta.-Blockers, such as acebutolol,alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol,pindolol and propranolol; cardiac inotropic agents, such as amrinone,digitoxin, digoxin, enoximone, lanatoside C and medigoxin;corticosteroids, such as beclomethasone, betamethasone, budesonide,cortisone acetate, desoxymethasone, dexamethasone, fludrocortisoneacetate, flunisolide, fluocortolone, fluticasone propionate,hydrocortisone, methylprednisolone, prednisolone, prednisone andtriamcinolone; diuretics, such as acetazolamide, amiloride,bendroflumethiazide, bumetanide, chlorothiazide, chlorthalidone,ethacrynic acid, frusemide, metolazone, spironolactone and triamterene,anti-parkinsonian agents, such as bromocriptine mesylate, lysuridemaleate, pramipexole, ropinirole HCl, and tolcapone; gastrointestinalagents, such as bisacodyl, cimetidine, cisapride, diphenoxylate HCl,domperidone, famotidine, lansoprazole, loperamide, mesalazine,nizatidine, omeprazole, ondansetron HCl, rabeprazole sodium, ranitidineHCl and sulphasalazine; histamine H, and H,-receptor antagonists, suchas acrivastine, astemizole, chlorpheniramine, cinnarizine, cetrizine,clemastine fumarate, cyclizine, cyproheptadine HCl, dexchlorpheniramine,dimenhydrinate, fexofenadine, flunarizine HCl, loratadine, meclizineHCl, oxatomide, and terfenadine; keratolytics, such as such asacetretin, calcipotriene, calcifediol, calcitriol, cholecalciferol,ergocalciferol, etretinate, retinoids, targretin, and tazarotene; lipidregulating agents, such as atorvastatin, bezafibrate, cerivastatin,ciprofibrate, clofibrate, fenofibrate, fluvastatin, gemfibrozil,pravastatin, probucol, and simvastatin; muscle relaxants, such asdantrolene sodium and tizanidine HCl; nitrates and other anti-anginalagents, such as amyl nitrate, glyceryl trinitrate, isosorbide dinitrate,isosorbide mononitrate and pentaerythritol tetranitrate; nutritionalagents, such as calcitriol, carotenes, dihydrotachysterol, essentialfatty acids, non-essential fatty acids, phytonadiol, vitamin A, vitaminB2, vitamin D, vitamin E and vitamin K, opioid analgesics, such ascodeine, codeine, dextropropoxyphene, diamorphine, dihydrocodeine,fentanyl, meptazinol, methadone, morphine, nalbuphine and pentazocine;sex hormones, such as clomiphene citrate, cortisone acetate, danazol,dehydroepiandrosterone, ethynyl estradiol, finasteride,fliudrocortisone, fluoxymesterone, medroxyprogesterone acetate,megestrol acetate, mestranol, methyltestosterone, norethisterone,norgestrel, oestradiol, conjugated estrogens, progesterone, rimexolone,stanozolol, stilbestrol, testosterone and tibolone; stimulants, such asamphetamine, dexamphetamine, dexfenfluramine, fenfluramine and mazindol;and others, such as becaplermin, donepezil HCl, L-thryroxine,methoxsalen, verteporfrin, physostigmine, pyridostigmine, raloxifeneHCl, sibutramine HCl, sildenafil citrate, tacrine, tamsulosin HCl, andtolterodine.

Preferred hydrophobic therapeutic agents include sildenatil citrate,amlodipine, tramadol, celecoxib, rofecoxib, oxaprozin, nabumetone,ibuprofen, terbenafine, itraconazole, zileuton, zafirlukast, cisapride,fenofibrate, tizanidine, nizatidine, fexofenadine, loratadine,famotidine, paricalcitol, atovaquone, nabumetone, tetrahydrocannabinol,megestrol acetate, repaglinide, progesterone, rimexolone, cyclosporin,tacrolimus, sirolimus, teniposide, paclitaxel, pseudoephedrine,troglitazone, rosiglitazone, finasteride, vitamin A, vitamin D, vitaminE, and pharmaceutically acceptable salts, isomers and derivativesthereof. Particularly preferred hydrophobic therapeutic agents areprogesterone and cyclosporin.

Suitable proton pump inhibitors for use in the present inventioninclude, without limitation, omeprazole, lansoprazole, rabeprazole,pantoprazole, esomeprazole, and mixtures thereof.

It should be appreciated that this listing of hydrophobic therapeuticagents and their therapeutic classes is merely illustrative. Indeed, aparticular feature, and surprising advantage, of the compositions of thepresent invention is the ability of the present compositions tosolubilize and deliver a broad range of hydrophobic therapeutic agents,regardless of functional class. Of course, mixtures of hydrophobictherapeutic agents may also be used where desired. These carrierattributes will also be equally effective as a delivery vehicle for yetto be developed hydrophobic therapeutic agents.

In certain embodiments, the suitable pharmaceutical agents for use inthe compositions of this invention include, without limitation, weakacid pharmaceuticals, weak acid pharmaceuticals or mixtures andcombinations thereof. Exemplary weak acid pharmaceuticals include,without limitation, anti-inflammatory pharmaceuticals, steroids,sterols, NSAID, COX-2 inhibitors, or mixture thereof. Exemplary weakbase pharmaceuticals include, without limitation, weak base antibiotics,caffeine, codiene, ephedrine, chlordiazepoxide, morphine, pilocarpine,quinine, tolbutamine, other weak base pharmaceutical agents and mixturesor combinations thereof. Exemplary anti-inflammatory pharmaceuticalsinclude steroidal anti-inflammatory drugs, non-steroidalanti-inflammatory drugs, acetaminophen and COX-2 inhibitors or mixturesand combinations thereof.

Suitable NSAIDS include, without limitation: (a) propionic acid drugsincluding fenoprofen calcium, flurbiprofen, suprofen, benoxaprofen,ibuprofen, ketoprofen, naproxen, and/or oxaprozin; (b) acetic acid drugincluding diclofenac sodium, diclofenac potassium, aceclofenac,etodolac, indomethacin, ketorolac tromethamine, and/or ketorolac; (c)ketone drugs including nabumetone, sulindac, and/or tolmetin sodium; (d)fenamate drugs including meclofenamate sodium, and/or mefenamic acid;(e) oxicam drugs piroxicam, lornoxicam and meloxicam; (f) salicylic aciddrugs including diflunisal, aspirin, magnesium salicylate, bismuthsubsalicylate, and/or other salicylate pharmaceutical agents; (g)pyrazolin acid drugs including oxyphenbutazone, and/or phenylbutazone;and (h) mixtures or combinations thereof.

Suitable COX-2 inhibitors include, without limitation, celecoxib,rofecoxib, or mixtures and combinations thereof.

Acid Labile Pharmaceuticals

Suitable acid labile pharmaceutical active agents include, withoutlimitation, peptides, proteins, nucleosides, nucleotides, DNA, RNA,glycosaminoglyacan, any other acid labile pharmaceuticals, or mixturesor combinations thereof. Examples of acid-labile drugs which may used inthe carrier systems disclosed herein are e.g.(+)-N{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-Nhydroxyurea,amylase, aureomycin, bacitracin, beta carotene, cephalosporins,chloromycetin, cimetidine, cisapride, cladribine, clorazepate,deramciclane, didanosine, digitalis glycosides, dihydrostreptomycin,erythromycin, etoposide, tamotidine, hormones (in particular estrogens,insulin, adrenalin and heparin), lipase, milameline, novobiocin,pancreatin, penicillin salts, polymyxin, pravastatin, progabide,protease, quinapril, quinoxaline-2-carboxylic acid,[4-(R)carbamoyl-1-(S-3-fluorobenzyl-2-(S),7-dihydroxy-7-methyloctyl]amide, quinoxaline-2-carboxylicacid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide,ranitidine, streptomycin, subtilin, sulphanilamide and acid-labileproton pump inhibitors like esomeprazole, lansoprazole, minoprazole,omeprazole, pantoprazole or rabeprazole. Digestive proteins such asamylase, lipase and protease may be included in disclosed carriersystems. Amylases, lipases and proteases which are suitable as digestiveenzyme supplement or digestive enzyme substitute in mammals,particularly humans, are preferred. Amylase, lipase and/or protease maybe derived from microbial or animal, in particular mammalian, sources.Pancreatin is a acid-labile drug. Other therapeutic proteins or peptidesmay be used with the disclosed carriers to increase bioavailability.Other therapeutic proteins may include, without limitation, insulin,erythropoietin, or fragments or derivatives thereof. Example ofglycosaminoglycan include, without limitation, heparin, or fragmentsthereof. The foregoing list of acid-labile drugs is not meant to beexhaustive, but merely illustrative as a person of ordinary skill in theart would understand that many other acid-labile drugs or combination ofacid-labile drugs could also be used.

Nutraceutical Agents

Suitable nutraceuticals for use in the compositions of this inventioninclude, without limitation, any nutraceutical agent that is capablewith the carriers of this invention. In certain embodiments, thenutraceutical agents are solid. In other embodiments, the nutraceuticalagents are oil soluble liquids or oil miscible liquids.

Biocompatible Oils

Suitable biocompatible oils include, without limitation, any oilapproved for a human, mammal or animal consumption by the FDA or othergovernmental agency. Exemplary biocompatible oils include, withoutlimitation, plant derived oils or animal derived oils or theirderivatives or synthetic oils. In certain embodiments, the natural oilsare oils rich in phospholipids such as lecithin oils from soy beans.Exemplary examples of plant derived oils or animal derived oils or theirderivatives or synthetic oils include, without limitation, essentialoils, vegetable oils an hydrogenated vegetable oils such as peanut oil,canola oil, avocado oil, safflower oil, olive oil, corn oil, soy beanoil, sesame oil, vitamin A, vitamin D, vitamin E, or the like, animaloils, fish oils, krill oil, or the like or mixture thereof.

In certain embodiments, the biocompatible oil is a neutral lipid.Suitable neutral lipid include, without limitation, any neutral lipidsuch as the triglyceride. For a partial listing of representativeneutral lipids, such as the triglycerides, reference is specificallymade to U.S. Pat. Nos. 4,950,656 and 5,043,329. Both saturated andunsaturated triglycerides may be employed in the present compositions,and include such triglycerides as tripalmitin (saturated), triolein andtrilinolein (unsaturated). However, these particular triglycerides arelisted here for convenience only, and are merely representative of avariety of useful triglycerides, and is further not intended to beinclusive.

Animal fats include, without limitation, lard, duck fat, butter, ormixture or combination thereof.

Vegetable fats include, without limitation, coconut oil, palm oil,cottonseed oil, wheat germ oil, soya oil, olive oil, corn oil, sunfloweroil, safflower oil, hemp oil, canola/rapeseed oil, or mixture andcombinations thereof.

Other Additives, Excipients or Adjuvants

The formulation or compositions of this invention can also include otherchemicals, such as anti-oxidants (e.g., Vitamin A, C, D, E, etc.), tracemetals and/or polyvalent cations (aluminum, gold, copper, zinc, calcium,etc.), surface-active agents and/or solvents (e.g., propyleneglycol/PPG, dimethy sulfoxide/DMSO, medium chain triglycerides/MCT,etc.), non-toxic dyes and flavor enhancers may be added to theformulation as they are being prepared to improve stability,fluidity/spreadability, permeability, effectiveness and consumeracceptance. These additives, excipients, and/or adjuvants may alsofunction as active agents.

Experiments of the Invention

The carriers of this invention and compositions including the carriersof this invention possess the capability of targeted release of anactive agent into the selected regions of gastrointestinal (GI) tract.Carrier-mediated targeted release is particularly useful for activeingredients that are: (a) injurious to the upper GI tract (esophagus,stomach, and duodenum), (b) acid labile, (c) impermeable/insolublecompounds GI fluids, (d) susceptible to first pass metabolism, and (e)cause stomach irritation, upset, or dyspepsia. In certain embodiments,the targeted release is a pH dependent release so that the activeagent(s) is (are) released minimally at low pH of the stomach (e.g., apH less about 3-<pH 3) and are efficiently released at higher pH of theupper duodenum (e.g., at pH greater than to or equal to 4 to 5). Incertain embodiments, the targeted release is a pH dependent release sothat the active agent(s) is (are) released minimally at low pH of thestomach (e.g., a pH less about 3-<pH 3) and upper duodenum (e.g., at pHgreater than to or equal to 4 to 5), and are efficiently released at thehigher pH of the small intestine in presence of high concentration ofbile. In certain embodiments, the pH dependent release of the activeagent(s) is due to the inclusion in the carrier of pH dependent releaseagents such as oils including at least one carboxylic acid group or atleast one oil soluble or miscible compound including at least onecarboxylic acid group. In other embodiments, the oils including at leastone carboxylic acid group or at least one oil soluble or misciblecompound including at least one carboxylic acid group are free fattyacids. Fatty acids are particularly useful for tailored release alongthe GI tract because most fatty acid are nonionized or neutral form atgastric pH, but are ionized at intestinal pH which enables them toselectively the active ingredient payload. The studies summarized inthis section provide evidence for use of carriers for 1) pH dependentrelease, 2) targeted dissolution along the GI tract, 3) targeted releaseenable reduction of GI toxicity of active agents, 4) targeted release ofa variety of active agents, and 5) use of pH dependent release carriersfor improving the bioavailability of active agents such as acid labileactives, insoluble compounds GI fluids and susceptible to first passmetabolism.

pH Dependent Release of Actives

Our prior studies have suggested that purified phosphatidylcholine (PC)(e.g., Phospholipon 90G) and a lecithin oil (e.g., Phosal 35SB (PS35SB))increase the partition of aspirin (Log P_(cyclohexane/0.1N HCl))) in apH dependent manner. The partitioning (Log P) value was maximal at 0.1 NHCl, with little or no modification in partitioning at neutral pH. Thesedata suggest a pH dependent partitioning of aspirin (ASA) when ASA isdispersed in a lecithin oil carrier (i.e., having attributes of LecithinNF). The pH dependent partitioning was thought to be due to either thecarrier or particular carrier components due to interactions between thecarrier and/or its components and the pharmaceutical agent (e.g.,NSAID). As lecithin is predominately a complex mixture of phospholipids,triglycerides, and free fatty acids, it was unclear if the free fattyacids inherently in the lecithin or the lecithin carrier conferred thepH sensitivity of the partitioning of aspirin. Therefore, the pHdependent changes in hydrophobicity afforded by a free fatty acid weretested by two methods; partitioning (Log P) and in vitro dissolution.

Preparation of ASA-FFA and FFA/PC Carrier Composition

In this study, ASA-FFA and FFA/PC carrier compositions having differingweight ratios of aspirin and FFA were prepared. The compositions wereprepared by admixing powdered ASA into each carrier and heating themixtures to a temperature of 35° C. for about 30 minutes. Thecomposition formulas are given in Table I.

TABLE I Make Up of ASA-FFA and ASA-FFA/PC Compositions ASA to CarrierCarrier Weight Weight Name Carrier Components Ratio Ratio ASA None N/A 010:1 ASA:SFFA Oleic Acid N/A 10:1   1:1 ASA:SFFA Oleic Acid N/A 1:1 1:10 ASA:SFFA Oleic Acid N/A  1:10  1% PC* 1:1 ASA:SFFA** OleicAcid/PC* 99:1 1:1  5% PC* 1:1 ASA:SFFA** Oleic Acid/PC* 95:5 1:1 10% PC*1:1 ASA:SFFA** Oleic Acid/PC*  90:10 1:1 ASA:PS35SB** PS35SB*** 45:30:111:1 (PL/TG/FFA) *phosphatidylcholine added as the purifiedphosphatidylcholine 90G (Lipoid LLC). **SFFA is soy free fatty acids(Peter Cremer Company). **an engineered lecithin oil (Lipoid LLC)containing about 45 wt. % phospholipids.

Free Fatty Acids Increases Partitioning of Aspirin (ASA) in a pHDependent Manner

The compositions of Table I were tested in a two phase partitioningsystem. In this system, the Log P value of aspirin (ASA) was measured intwo immiscible solvents: cyclohexane and 0.1N HCl. Cyclohexane was usedto mimic a purely hydrophobic surface such extracellular gastric mucosa.HCl (0.1N) was used to simulate gastric fluid. In U.S. Pat. Nos.4,950,656, 5,043,329, 5,763,422, and 5,955,451, triglycerides incombination with zwitterionic phospholipids were used to reducetoxicity, to increase the cyclohexane solubility of NSAIDs at pH's abovetheir pKa's, and to improve NSAID efficacy. U.S. Pat. Nos. 5,763,422,and 5,955,451 specifically demonstrated that DPPC increased thesolubility of ASA in cyclohexane at pH's above their pKa's and that theaddition of triglycerides such as trioleate and tripalmitin enhancedthis increased solubility. These prior art teachings showed thatphospholipids and mixture of phospholipids and triglycerides increasesASA solubility at pH's near the pKa of ASA in cyclohexane, similar tothe operation of a phase transfer agent. However, these patents includedno teaching that free fatty acids would function as acceptable carriersfor pharmaceutical agents such as ASA or that they would be carrierscapable of pH dependent release of ASA.

We show here that Log P values of ASA-SFFA formulations may be tailoredto have Log P values comparable to 1:1 weight ratio formulations of ASAand Phosal 35SB (PS35SB), an engineered lecithin oil. We have also shownthat (1) ASA carriers composed of FFA alone had Log P values comparableto the ASA-PS35SB formulations, (2) ASA carriers with low levels ofphospholipids (e.g., ≦10 wt. %) had Log P values comparable toASA-PS35SB formulations; and (3) ASA carriers without FFA had releasecharacteristics similar to immediate release aspirin. Thus, the carriersmay be tailored to release active agents into different pH environmentsand/or the level of release may be modulated within given regions of theGI tract based on: (1) the ratio of the FFA and the secondary complexingagents or other carrier components (e.g., FIG. 3 and FIG. 14) and/or (2)the ratio of the carrier to the active agents (e.g., FIG. 1). We believethat the Log P values are predictive of improved NSAID GI safety orreduced NSAID GI toxicity as is shown in the animal study describedherein (e.g., FIGS. 12 and 13).

Referring now to FIG. 1, soy pure FFA (SFFA) alone increases thepartitioning of aspirin in a concentration dependent manner into anwater immiscible phase; thus, the ratio of active agents to carriermodulates the partitioning characteristics of the composition. Acomposition including 1:1 weight ratio of aspirin and a 100% FFA carrierhad similar Log P values as a 1:1 weight ratio of aspirin and a highphospholipid lecithin oil carrier, PS35SB (e.g., ˜45% phospholipid),suggesting that the 100% FFA carrier may facilitate increased lipidsolubility of aspirin similar to that of a high phospholipid lecithincarrier. We also show that the FFA in the carrier interacts with theaspirin at the molecular level as shown by FTIR data herein. Suchinteractions may be in the form of non-covalent association complexesbetween the aspirin and the FFA. We also demonstrate below that 100% FFAor oil based carriers including a sufficient amount of FFA are capableof pH dependent release of pharmaceutical agents such as NSAIDs. Thisdata and the other data set forth herein show that carriers withsufficient pH dependent release agents such as FFAs are capable ofreleasing NSAIDs in a pH specific fashion (i.e., the compositions haveminimal release at low pH and efficient release at higher pH) should begeneralizable to pharmaceutical and/or nutraceutical agents that areneutral in their solid form, are weak acids, and potentially weak bases.

Referring now to FIG. 2, increased FFA-induced partition of aspirin intoa water immiscible solvent such as cyclohexane is pH dependent. Theincreased partitioning of aspirin across a pseudo-hydrophobic membraneby FFA suggests that FFA alone may modify the physicochemical and/orrelease behavior of aspirin. This observation further suggests that abinary ratio of aspirin and FFA may improve the gastrointestinal safetyof aspirin in a similar manner as found in high phospholipid lecithinoil carriers such as PS35SB. Although not meaning to be tied to anyparticular theory, the interaction of FFA and ASA may involve theinteraction between the carboxylic acid group of aspirin and thecarboxylic acid group of the FAA. Carriers having high concentrations ofFFA and no or low concentrations of phospholipids appear to have similarcharacteristics to high phospholipid lecithin oil carriers. Thesecarriers contain approximately 46 wt. % phospholipids and are derivedfrom crude soy bean lecithin. They are engineered lecithin oil in thatthe original triglycerides have been removed and replaced by sunfloweroil and approximately 11 wt % of a mixture of oleic acid and linoleicacid. Two such lecithin oil products are Phosal 35 SB (PS35SB) andEpikuron (135F). This FFA-aspirin behavior supports compositions thatwould include no or unusually low levels of phospholipids, levels ofzero to less the 10 wt % phospholipid and no or unusually low levels oftriglycerides, levels of zero to less the 10 wt % neutral lipids.Alternatively, we believe that FFA may act as a pH dependent releaseagent due primarily to the nature of FFA. At low pH, FFAs are unchargedand act essentially as a biocompatible oil. However, as the pH israised, FFAs ionize forming FFA salts, which are known surfactants.Surfactants are known to increase the release of pharmaceutical agentssuch as NSAID from oil based carriers as we use a surfactant rich buffersystem to perform NSAID dissolution such of pr-commercial NSAID-PS35SBformulations.

In U.S. patent application Ser. No. 12/883,873, improved NSAID GI safetywas mediated by oil based carriers including greater than 10 wt. %phospholipid: in fact, the compositions used in the examples includedabout 46 wt. % phospholipid as that is the approximate phospholipidcontent of PS35SB, a high phospholipid lecithin oil carrier. Moreover,the use of a carrier containing any amount of phospholipid to augmentthe bioavailability and toxicity of an NSAID in a tailored matter wasnot contemplated. As FFA-ASA compositions have similar Log P valuescompared to PS35SB-ASA compositions, we determined that a new class ofcarriers for pharmaceutical and/or nutraceutical agents such as NSAIDsmay be developed using FFA as a key constituent for a pH controlledrelease of the active agents. In the data that follows, we demonstratethat carriers including FFAs efficiently release the pharmaceuticalagents and/or nutraceutical agents at a pH greater than about pH 3,while non-FFA containing oil based carriers efficiently release theactive agents at a pH less than about 3.

We have also determined that FFA carriers may be modified by theaddition of low levels of phospholipid giving rise to similar Log Pvalues when aspirin is the NSAID. The fact that these FFA carriers havesimilar Log P values for ASA is unexpected in light of the teaching inthe prior art, where the phospholipid content was assumed to be theoperative constituent in lowering GI toxicity of NSAIDs. As shown inFIG. 3, high FFA carriers were effective carriers of PC and providedsimilar partition values for aspirin with phospholipid (PC here)contents between 5 wt. % and 10 wt. % compared to a PS35SB carriercontaining about 45 wt. % PC; and thus, the carrier are tailorable bythe ratio of FFA to secondary complexing agents in the carrier. Thesedata suggest that phospholipid levels required to mediate GI safetycould be markedly reduced from approximately 45 wt. % phospholipid to≦10 wt. %. The data also suggests that FFA carriers may be effectiveNSAID carriers in the absence of any phospholipid. FFA carriers havinglow phospholipid amounts would also have added stability and costbenefits over existing by phospholipid carriers, which have been shownto undergo considerable phospholipid degradation—loss of the ester sidechains.

The fact that carriers including low levels of or no phospholipid behavein a similar manner to Phosal 35 SB (PS35SB), a carrier includingapproximately 45 wt. % phospholipid, is wholly unexpected. Even moreunexpected is that ASA partitioning in a pure FFA carrier shows definitepH dependencies similar to PS35SB. We believe that we now havealternative carriers for use with pharmaceutical and/or nutraceuticalagents that avoid the complications of relatively expensive,hydrolytically, and thermally unstable phospholipids.

We illustrate some of the properties of the carries of this invention byreference to aspirin (ASA) carrier compositions, where the carriersinclude neutral lipids, free fatty acids, and phospholipids. One type ofhigh phospholipid carrier is a triple strength lecithin product sold asPhosal 35 SB. Up to now it had been assumed that the NSAID complexingagents in carriers containing phospholipids were phospholipids, of whichphosphatidylcholine is present in the greatest concentration. However,we believe that the free fatty acids may comprise a second group ofcomponents that may form reversible complexes with ASA. We also believethat neutral lipids may also form a third group of components that mayform reversible complexes with ASA. Besides providing components fornon-covalent complexation of ASA, the other carrier components may playa role in the activity of the ASA complexes including ASA-PC complexesand in the dispersal of the compositions in water. The present study isdirected to dissolution procedures pertaining to a triple strengthlecithin-ASA composition to assess pH dependent release to simulate APIrelease across the GI tract.

pH Dependent Increased Hydrophobicity Results in pH DependentDissolution

In this analysis, the release of ASA from the triple strength lecithinoil PS35SB carrier-ASA composition (PS35SB-ASA) was compared to that ofimmediate release aspirin. PS35SB-ASA was filled into hard shelledcapsules and immediate release aspirin tablets were tested. Dissolutionrates were measured in a United States Pharmacopia (USP) Type IIapparatus using the various media preparations.

In this analysis, the release of ASA from PS35SB-ASA was compared tothat of plain aspirin tablets. The PS35SB-ASA composition filled intohard shelled capsules and plain aspirin tablets were tested. The releaseof aspirin from the two dose forms were evaluated per USP <711> using aType II dissolution apparatus, at 37° C. in a vessel containing 900 mLof various citrate phosphate buffers at 3.5, 4.5, 5.5, 6.9, 7.4, at 150rpm paddle speed.

The rate of release was monitored by sampling the dissolution vessels at5, 10, 15, 30, 45, 60, 75, and 90 minutes, and infinity samples. Thefraction of aspirin released and dissolved from the two dose forms wasmonitored by HPLC.

The HPLC method used to measure the release of acetylsalicylic acid andsalicylic acid is isocratic elution at 1.2 mL per minute, with a60/40/0.2 water/acetonitrile/phosphoric acid mobile phase. The columnused was an ODS3 “Inertsil”, 5 μm, 250×4.6 mm by ES Sciences. Standardswere prepared by dissolving and diluting aspirin, manufactured byRhodia, into mobile phase.

Referring to FIG. 4, dissolution profiles of immediate release ASAtablets at different pH values is shown, while FIG. 5 shows thedissolution profiles of a PS35SB-ASA composition at different pH values.

The immediate release aspirin tablets began to disintegrate immediatelywhen introduced to the dissolution and were completely dissolved in thefirst five minutes for all pH levels.

In contrast, the PS35SB-ASA filled capsules showed shell disintegrationstarting after approximately ten minutes. Upon rupture of the capsule,fill material was released, dispersed and dissolved in a pH dependentmanner as show in FIG. 5.

The aspirin released from PS35SB-ASA composition (see FIG. 5) clearlyshowed an increase with increasing pH, suggesting that the release ofaspirin from the lecithin oil matrix is pH dependent. While notintending to be bound by any theory, it is thought that the increasedrate of release at higher pH is due to the ionization of carboxylic acidgroup of aspirin. Thus, the aspirin release from the PS35SB carrier ormatrix increases with pH, as demonstrated above in FIG. 5. However, ithas become clear that the pH dependent properties of PS35SB may besolely due to the presence of a sufficient amount of fatty acids in thePS35SB carrier as carriers including only triglycerides andphospholipids showed reduced to no pH dependent characteristics for ASAillustrated in FIG. 6.

To determine if the free fatty acids in the lecithin oil PS35SB mediatedthe pH dependent release, the release of aspirin from four preparationscontaining 325 mg of aspirin in tablet or capsule form as summarized inTable II were measured in simulated gastric fluid (0.1HCl) per USP<711>.

TABLE II Capsule Fill Formulas Component A B C Aspirin 49 49 49 PS35SB*49 Carrier Composition PC 19.6** 19.6 20.58** TG 29.4*** 14.7 13.72***FFA 5.4 14.7**** Other^(†) 9.3 Silicon Dioxide 2 2 2 Total 100 100 100*Phosal 35SB an engineered lecithin oil - component break down shown ingrey based on 49 wt. % Phosal 35SB. **Purified soy phosphatidylcholine(S100, Lipoid LLC) ***Triglycerides derived from Soy bean oil. ****FFAused was oleic acid (Croda) ^(†)other ingredients found in Phosal 35SBFormulas A-C were prepared by admixing ASA into the carrier at 40° C.with mixing as described herein. The lecithin oil contains approximately40 wt. % phosphatidylcholine, 40 wt. % triglycerides, 13 wt. % freefatty acids. As shown in FIG. 6, release of aspirin from the lecithinoil was minimal. As the release from the TG/PC only carrier was rapidand is highly attenuated by the addition of a FFA: thus, the pHsensitive release afforded by the lecithin oil as described in FIG. 5 isdue primarily to the presence of the FFA.

Targeted Release of Aspirin Along the GI Tract

As previously shown, the pH sensitive hydrophobicity results in pHsensitive release and dissolution. As the physiological milieu isdramatically different between stomach, upper duodenum and theintestine, the targeted release as assessed by in vitro dissolution ofthree carriers described in Table III were evaluated in simulatedgastric, duodenal and intestinal fluids dissolution characteristics offormulations including an oleic acid carrier, an oleic acid/2.5 wt. % PCcarrier, and PS35SB carrier. The formulations were prepared by addingthe ingredients listed in Table III and stirring the mixtures as 35° C.for 30 minutes, except for the ASA formulation that is a tablet, whilethe other formulations are filled into hypermellose capsules.

TABLE III Ingredients Used in the Formulations Formulation ComponentWeight (g) wt. % ASA Aspirin 19.6000 100 P1 Oleic Acid 19.6113 49.00S100* 0.0000 0.00 Aspirin 19.6142 49.00 Silicon Dioxide 0.8002 2.00 P2Oleic Acid 18.7541 46.51 S100* 1.0072 2.50 Aspirin 19.7604 49.00 SiliconDioxide 0.8046 2.00 AC2 PS35SB** 25.7060 49.00 Aspirin 25.7077 49.00Silicon Dioxide 1.0494 2.00 *purified soy phosphatidylcholine (LipoidLLC) **an engineered lecithin oil carrier

Referring now to FIG. 7, the dissolution profiles in of ASA, P1, P2 andAC2 were tested in simulated gastric fluid consisting of 0.1 N HClhaving a pH 1 in a USP Type II apparatus at 37° C. at 150 rpm paddlespeed.

Referring now to FIG. 8, dissolution profiles in “simulated upperduodenal fluid” pH 4.5 at 150 rpm.

Referring now to FIG. 9, dissolution profiles in “simulated intestinalfluid” pH 7 dissolution buffer (bicarbonate buffer with 20 mM cholicacid and 1% pancreatin) at 150 rpm. This media is a fed variant of USPintestinal fluid (pH 7.2 phosphate buffer, 1% pancreatin).

Referring now to FIGS. 10A&B, a side by side comparison of averagedissolution profiles of 0 wt. % PC and 2.5 wt. % PC formulations indifferent media: 0.1 N HCl, a dissolution buffer (bicarbonate bufferwith bile acids and enzymes), an acetate buffer, and a phosphate buffer.

The above dissolution data provides compelling support for the use offatty acid based carriers (i.e., carriers that include a sufficientamount of a fatty acid to render the carrier capable of pH dependentrelease) as carrier for active agents that are known to have GI toxicitysuch as NSAID, active agents that are degraded in low pH environmentssuch as in gastric fluids, active agents that are better absorbed in theupper part of the small intestines, and/or active agents that aretargeted for release after passing through the stomach, but that do notrequire release at high pH found in the lower GI tract.

Referring now to FIG. 11, a picture of the upper GI track—stomach tosmall intestines (duodenum, jejunum and ileum) is provided to show themarked differences in physicochemical properties of the various sectionsof the GI tract. The differences in pH and bile acids concentration andcomposition, digestive enzymes could be exploited to enable targetedrelease of actives using the various lipid carriers. The present ASAFormulas including FFA clearly show pH dependent ASA release inaccordance with the pH change from the stomach through the various partsof the small intestine. Thus, the carriers including an amount of FFAsufficient to reduce or minimize ASA release in the stomach or at lowpH, while increasing or maximizing ASA release in the small intestine asthe pH increases along the distal part of the small intestine. Thecarriers of this invention including an amount of FFA are, therefore,well suited for tailored release of active agents such as pharmaceuticaland/or nutraceutical agents in the duodenum with reduced or minimizedrelease of the active agents in the stomach. As will be shown herein,the pH characteristics of the carriers of this invention including thissufficient amount of FFA are generalizable to NSAID and based on thefact that solid materials are dispersed in the carriers, the carriers'pH characteristics should be generalizable to all solid active agentsdispersed in these carriers.

Targeted Release of Aspirin Along the GI Tract May Decrease GastricDamage

As the FFA alone, FFA in combination with low PC, lecithin provideselective release and dissolution of aspirin in simulated intestinalfluids and aspirin release in the stomach is known to induced erosivedamage, the ability of selective carrier mediated release on gastric andintestinal damage was evaluated in the rat. Rats were administered byoral gavage mini-capsules containing aspirin at 40 mg/kg in carrierformulations in Table VIII, along with a methylcellulose negativecontrol, and pulverized immediate release aspirin.

The experimental controls used in this study include: (1) a controlcomposition (NAC) comprising Methyl Cellulose from Sigma ChemicalCompany, Product No. M-0512, Lot No: 74F-0466, which was stored incontrolled ambient temperature; (2) 325 mg OTC Aspirin (AC1) fromWalgreen Co, Product No. P53405, and (3) 325 mg Aspirin in Phosal 35SBcarrier (AC2).

Two compositions P1 and P2 of this invention were prepared along withAC2. AC2, P1 and P2 had the ingredient formulations shown in Table IVand were stored during the study under controlled ambient temperatureand protected from light.

TABLE IV Ingredient Formulations Formula Component Weight (g) IngredientP1 Lipid Carrier 19.6113 Oleic Acid Active Ingredient 19.6142 AspirinViscosity Modifier 0.8002 Cab-o-Sil M5P P2 Lipid Carrier 1.0072 S100(Purified Soy PC) 18.7541 Oleic Acid Active Ingredient 19.6142 AspirinViscosity Modifier 0.8002 Cab-o-Sil M5P AC2 Lipid Carrier 25.7060 Phosal35SB Active Ingredient 15.7077 Aspirin Viscosity Modifier 1.0494Cab-o-Sil M5P

The formulations P1, P2, and AC2 were prepared by: 1) lipid componentswere mixed and incubated at 40° C. for one hour with occasional mixingto insure lipid carrier homogeneity; 2) aspirin was mixed into the lipidcarrier, 3) a viscosity modifier was added to the lipid carrier/aspirinmixtures; 4) the formulations were mixed until homogeneous and incubatedat 40° C. for 60 minutes; and 5) the formulations were stored at ambientconditions and mixed well before use.

Forty (40) male Sprague-Dawley rats, approximately 10 weeks of age, wereused in this study. Animals were randomly distributed among 5 treatmentgroups, 8 rats per group.

TABLE V Animals Randomized to Each Treatment Group Aspirin Dose AspirinGroup (mg/kg/day) (mg/mini-cap) # Rats Dosed NAC* 0 0 8 AC1 40 10.14 and10.79 8 P1 40 19.83 and 19.80 8 P2 40 19.75 and 19.67 8 AC2 40 20.32 and19.75 8

Test articles were packed into mini-capsules such that one mini-capsulewould provide an intragastric dose of aspirin of 40 mg/kg/day peranimal. For preparation of OTC Aspirin, tablets were pulverized using amortar and pestle and packed into mini-capsules. For P1, P2, and AC2, anappropriate amount of fill material (based on the aspirin content of thefill) was added to the mini-capsules. Dosing formulations were preparedfor a 3-day treatment based on the assumption that each animal wouldgain an average of 3.0 g in body weight during the 3-day experimentalperiod. For example, the mini-cap containing the initial dose of aspirinwas assembled for a rat of average Day 1 body weight+3.0 g.

Animals were fasted (with ad libitum access to water) from 8 am to 3 μmprior to dosing; wire-bottom cages were required to prevent animals fromeating any bedding or fecal pellets. Doses of aspirin and P1, P2, andAC2 were administered by oral gavage for 3 consecutive days (Study Days1, 2, and 3) between 2 μm and 3 μm to maximize the potential effects ofthe study drugs on the stomach, at 40 mg NSAID per kg body weight perday.

Animals were maintained in the fasting state for 1 hour after dosing:food was then available ad libitum until the next morning.

After 3 day of treatment, the rats were sacrificed and the followingtissues were collected for analyses stomach, small intestine (jejunumand ileum). The extent of erosive damage in the stomach was evaluatedmicroscopically and level of gastric or intestinal bleeding wasevaluated by measuring luminal fluid hemoglobin.

Gastric examination was performed under a dissecting microscope forevidence of erosions and ulcers and dosing-related injury. Specifically,following the wash with distilled water for Hb assay, the stomach wasopened by an incision along the lesser curvature, rinsed with normalsaline, and blotted dry with #2 filter paper. Gastric lesions observableunder the dissecting microscope that could not be removed by rinsing theluminal surface of the dissected stomach with saline were counted andmeasured. Gastric lesion scoring by animal was recorded.

Two types of gastric lesions were observed: linear and small dot(pinpoint): (1) Pinpoint lesions (0.1 to 1.0 mm in the longestdimension) were each assigned a score of 1 mm²; and (2) Linear lesions(more than 1 mm in length) were measured in length and width. The lesionwas assigned a score equal to the area of the lesion in mm² [length(mm)×width (mm)].

The gastric lesion score of an animal was determined to be the sum ofthe scores of the pinpoint and linear lesions, an estimate of the totalarea of gastric lesions. The gastric lesion score of a treatment groupwas determined to be the average of the gastric lesion scores of theanimals in that group.

Hemoglobin (Hb) concentrations in gastric and small intestinal washesand in sonicated solutions of fecal pellets were determined by thebenzidine method and measuring optical density (OD) at 515 nm.

Targeted Release of Aspirin Reduces Gastric Damage

Gastric lesions, defined as pinpoint or larger (linear) lesions ongastric mucosa observable under a dissecting microscope, were measuredand scored as described below. Gastric lesion scores for each treatmentgroup are presented in FIG. 12. The gastric lesion score (FIG. 12) waslower in all groups treated with P1, P2, and AC2 than in those treatedwith AC1.

A significant difference between the gastric lesion scores was notedbetween groups [F(4, 35)=10.42, p<0.0001, Tukey's HSD]. The gastriclesion score in animals treated with AC1 (15.5±3.7) was significantlyhigher than in groups treated with P1 (3.6±1.2; p<0.01), P2 (5.3±1.5;p<0.01), AC2 (1.8±0.7: p<0.01), or in the Control group (0; p<0.01). Thegastric lesion score in the control NAC was not different from groupstreated with P1, P2, and AC2. No significant differences were noted ingastric lesion scores among the groups treated with P1, P2, and AC2.This reductions in gastric erosive damage by P1, P2, and AC2 was notaccompanies by any obvious significant changes in bleeding as luminalhemoglobin levels, except that Pt treated rats had significantly lowerHb concentration than AC1 as shown in FIG. 13. These data suggesttargeted release of aspirin to the intestine by either lecithin oil, afree fatty acid alone, or a free fatty acid with a low amount ofphospholipid results in reduced gastric damage.

P1, P2, and AC2 have been show to provide pH dependent and as suchselective release in small intestinal fluid with minimal release ofaspirin in gastric fluid (FIG. 7-9). With all three formulationsproviding similar improvement in erosive damage to stomach, these dataindicate that a carrier comprising of a FFA provides targeted releasealong GI tract and such targeted release can minimize GI Damage. Thisobservation is particularly unexpected because FFA alone have thepropensity to induce upper GI injury.

Use of Carriers to Increase Bioavailability of Poorly PermeableBiologically Active Agents and Other Applications

Aspirin is poorly soluble at gastric pH but highly permeablepharmaceutical active agent. In contrast, in the intestine aspirin ishighly soluble but poorly permeable across epithelial cells. Theoctanol/0.1 N HCl system has been used to assess the relative solubilityand partitioning of aspirin across intestinal epithelial cells forpoorly permeable compounds using aspirin a model compound.

In this study, the partitioning behavior of carrier compositions havingdifferent ratio of oleic acid, a free fatty acid (FFA) to a purifiedtriglyceride (TG) in an octanol/0.1 N HCl partitioning system wasinvestigated. The carriers were admixed with aspirin (ASA) to form 1:1weight ratio of ASA to carrier compositions. The admixing preparationprocedure was substantially similar to the admixing methods set forthabove. The carriers included: (1) 100 wt. % FFA designated ASA FFA, (2)80 wt. % FFA and 20 wt. % TG designated ASA 80 FAA:20 TG, (3) 60 wt. %FFA and 40 wt. % TG designated ASA 60 FAA:40 TG, (4) 40 wt. % FFA and 60wt. % TG designated ASA 40 FAA:60 TG, (5) 20 wt. % FFA and 80 wt. % TGdesignated ASA 20 FAA:80 TG, and (6) 100 wt. % TG designated ASA TG. Theformulations were prepared using two different triglyceride types: along chained triglyceride (LCT) derived from soybean oil having C₁₆-C₂₀side chains and a middle chain triglyceride (MCT) having C₆-C₁₂ sidechains such MIGLYOL® 812 (a registered trademark of Sasol NorthAmerica).

Referring now to FIG. 14, the partitioning data clearly shows thatmodifying the ratio of FFA to components of the carrier (e.g., TG)modulates the partitioning across a simulated gastrointestinal membrane.Moreover, the partitioning is further controlled by chemicalcharacteristics or selection of the other components of the carrier. Forexample, the chain length of glycerides (e.g., TO) is also an importantfactor in modulating partitioning. These findings indicate two importantpotential applications of a FFA containing carrier: 1) to increasebioavailability of poorly permeable compounds across gastrointestinalmembranes, and 2) enable targeting absorption of actives to vialymphatic circulation and avoid first pass loss. As the Log P_(octanol)increases in the presence of a FFA, and higher Log P P_(octanol) isknown to be associated with improved bioavailability of poorly permeableactives, a carrier comprising free fatty acids may be used to improvethe bioavailability of poorly permeable compounds.

As the chain length of a TG is a known factor for lymphatic partitioningof active agents, the combined use of long chain (C₁₆ or greater) FFAand a long chain (C₁₆ or greater) TG could enable targeted release alongGI tract coupled with improved lymphatic partitioning. With increasedlymphatic absorption of an active, the extent of first pass loss couldbe decreased by decreasing fraction of orally administered biologicallyactive agents from absorption into the mesenteric circulation and theconsequent first pass metabolism in the liver.

FTIR Study of Various ASA Formulations

Referring now to FIG. 15, FTIR spectrum of pure aspirin (ASA), 1:1weight ratio formulation of ASA and PS35SB, 1:1 weight ratio formulationof ASA and linoleic acid, and 1:1 weight ratio of ASA and trioleate areshown in collective plot so that interaction behaviors between ASA andthe different carriers may be compared. First, it is apparent that ASAinteracts with all three carriers. Put another way, the three carrierscause shifts and spectral feature changes of the ASA ester andcarboxylic acid peaks, with the greatest shifts seen for the acid peak,where all carriers shift the acid absorption peak to a higher reciprocalcentimeter value. We believe that these interactions between ASA and thecarrier components may have some influence on carriers properties suchas partitioning properties, dissolution properties, pH dependent releaseproperties, and/or other properties. As the carrier properties aremediated by modification the inonizable free carboxylic acid groupaspirin, it may be possible to generalize the carrier mediated-targetedrelease to all weak acids. Therefore, the pH dependent change inhydrophobicities for several structurally diverse weak acid NSAIDs wereevaluated.

Generalizability of Carrier-Targeted Release to all Weak AcidBiologically Active Agents

Salicylic Acid

Solvation/Evaporation Method Vs. Admix Method Study

In this set of experiments, we found that the method of preparing thecompositions is not critical to the behavior of the resultingcompositions. Prior art suggested that the method of preparation wouldresult in significant changes in the behavior of the carriers. Theseexamples show that for carrier including a sufficient amount of FFA torender the carriers pH dependent, the compositions may be prepared by asimple admixing of ingredients together in the absence of a solvent orsolvent system or may be prepared by dissolving the components in asolvent or solvent system followed by solvent removal. Of course, thesemethod all are performed in the absence of added water, i.e., theingredients and solvent are generally water free or include only minimalor residual amount of water. Said another way, the methods used toprepare the compositions of this invention are non-aqueous, even thoughsome of the solvent may be water miscible such as ethanol. Thus, thecompositions formed by admixing or solvent dissolution followed bysolvent removal are oil based compositions including only minimal wateror residual water concentrations and are generally oil dispersions ofactive agents in an oil based carrier.

SA Formula A

This example illustrates the preparation by admixing of a compositionincluding a 1:1 weight ratio of salicylic acid (SA) and a carriercomprising about 40 wt. % of a purified phosphatidylcholine (PC) and apure triglyceride (TG) designed SA Formula A.

SA Formula A was prepared by admixing 50 wt. % SA into a carriercomprising 30 wt. % triglycerides derived from Soy bean oil and 20 wt. %of purified phosphatidylcholine at a temperature of about 40° C. forabout 30 minutes as described above.

SA Formula B

This example illustrates the preparation by admixing of a compositionincluding a 1:1 weight ratio of salicylic acid (SA) and a carriercomprising the lecithin oil Phosal 35SB (PS35SB) designed SA Formula B.

SA Formula B was prepared by admixing 50 wt. % SA into a carriercomprising PS35SB at a temperature of about 40° C. for about 30 minutesas described above.

SA Formula C

This example illustrates the preparation by admixing of a compositionsincluding a 1:1 weight ratio of salicylic acid (SA) and a carriercomprising 42 wt. % of a purified phospholipid, LIPOID® S100 (aregistered trademark of Lipoid LLC), 28 wt. % of a purified triglyceride(TG) (Spectrum Chemical Manufacturing Corporation), and 30 wt. % ofoleic acid (Spectrum Chemical Manufacturing Corporation) designed SAFormula C.

SA Formula C was prepared by admixing 50 wt. % SA into a carriercomprising 14 wt. % triglycerides derived from Soy bean oil, 15 wt. %oleic acid and 21 wt. % of purified phosphatidylcholine at a temperatureof about 40° C. for about 30 minutes as described above.

SA Formula D

This example illustrates the preparation by admixing of a compositionsincluding a 1:1 weight ratio of salicylic acid (SA) and a carriercomprising 5 wt. % of a purified phospholipid, 46.5 wt. % of a purifiedtriglyceride (TG) and 48.5 wt. % of oleic acid designed SA Formula D.

SA Formula D was prepared by admixing 50 wt. % SA into a carriercomprising 23.25 wt. % triglycerides derived from Soy bean oil, 24.25wt. % oleic acid and 2.5 wt. % of purified phosphatidylcholine at atemperature of about 40° C. for about 30 minutes as described above.

Table VI tabulations the SA Formulas compositions in weight percentages.

TABLE VI Formula Composition for Salicylic Acid (SA) Study SA SA SAComponent Formula A Formula B Formula C SA Formula D SA 50.0 wt. % 50.0wt. % 50.0 wt. %  50.0 wt. % PS35SB* 50.0 wt. % PC** 20.0 wt. % 20.0 wt.% 21.0 wt. %  2.5 wt. % TG*** 30.0 wt. % 15.0 wt. % 14.0 wt. % 23.25 wt.% Oleic Acid  5.5 wt. % 15.0 wt. % 24.25 wt. % Other^(†)  9.5 wt. %*Phosal 35SB an engineered lecithin oil - component break down shown ingrey based on 50 wt. % Phosal 35SB **Purified phosphatidylcholine***Triglycerides derived from Soy bean oil ^(†)other ingredients foundin Phosal 35SBPartitioning Study of SA Vs. SA Formulas A-D

In this study, pure salicylic acid (SA) partitioning between cyclohexaneand water versus salicylic acid partitioning between cyclohexane andwater in SA Formulas A-D was investigated at pH 1 and at pH 7 simulatinggastric fluids and duodenum fluids. The study was conducted by addingeither SA, SA Formulas A-D into a cyclohexane/water partitioning systemand measuring the differential partitioning of SA between the two phaseas the value Log P.

Referring now to FIG. 16, it is clear that SA partitions differently atpH 1 versus pH7. SA has a Log P of −1.11 at pH 1 and a Log P of 0.00 atpH 7. The partitioning of SA in SA Formulas A-D between cyclohexane andwater at pH 1 gives rise to Log P values that are less negative than theLog P value for SA at pH 1. The partitioning of SA in SA Formulas A-Dbetween cyclohexane and water at pH 7 gives rise to Log P values thatare much more negative than the Log P value for SA at pH 7.

Dissolution Study of SA Vs. SA Formulas A-C in a Two Stage DissolutionSystem

In this study, pure salicylic acid (SA) dissolution versus salicylicacid dissolution in SA Formulas A-C was investigated using a two stagedissolution procedure. The procedure related to measuring SA dissolutionin a pH 1 dissolution medium comprising 0.1 N HCl to simulate gastricfluids with mechanical stirring at 75 rpm stirring speed. After 60minutes, the pH of the medium was adjusted from pH 1 to pH 7.2 by theaddition of phosphate buffer to a final concentration of 0.05 M whilemaintaining the same stirring rate. The dissolution was represented as %LC, which is the percentage of SA that dissolves into the media.Measurement were made at 10 minutes, 20 minutes, 30 minutes, 50 minutes,60 minutes, 70 minutes, 90 minutes, 110 minutes, 120 minutes, 150minutes, and 180 minutes.

Naproxen

Preparation of NAP Formula A-D

NAP Formulas A

This example illustrates the preparation by admixing of a compositionincluding a 1:1 weight ratio of naproxen (NAP) and a carrier comprisingabout 40 wt. % of a purified phosphatidylcholine (PC) and a puretriglyceride (TG) designed NAP Formula A.

NAP Formula A was prepared by admixing 50 wt. % NAP into a carrierincluding 30 wt. % triglycerides derived from Soy bean oil (SpectrumChemical Manufacturing Corporation) and 20 wt. % of purifiedphosphatidylcholine from LIPOID® S100 (a registered trademark of LipoidLLC) at a temperature of about 40° C. for about 30 minutes as descriedabove.

NAP Formula B

This example illustrates the preparation by admixing of a compositionincluding a 1:1 weight ratio of naproxen (NAP) and a carrier comprisingthe lecithin oil PHOSAL 35SB (PS35SB) (a registered trademark of LipoidLLC) designed NAP Formula B.

NAP Formula B was prepared by admixing 50 wt. % NAP into a carriercomprising 50 wt. % PS35SB at a temperature of about 40° C. for about 30minutes as described above.

NAP Formula C

This example illustrates the preparation by admixing of a compositionsincluding a 1:1 weight ratio of naproxen (NAP) and a carrier comprising42 wt. % of a purified phospholipid (Lipoid LLC), 28 wt. % of a purifiedtriglyceride (TG) (Spectrum Chemical Manufacturing Corporation) and 30wt. % of oleic acid (Spectrum Chemical Manufacturing Corporation)designed NAP Formula C.

NAP Formula C was prepared by admixing 50 wt. % NAP into a carriercomprising 14 wt. % triglycerides derived from Soy bean oil (SpectrumChemical Manufacturing Corporation), 15 wt. % oleic acid (SpectrumChemical Manufacturing Corporation) and 21 wt. % of purifiedphosphatidylcholine (Lipoid LLC) at a temperature of about 40° C. forabout 30 minutes as described above.

NAP Formula D

This example illustrates the preparation by admixing of a compositionsincluding a 1:1 weight ratio of naproxen (NAP) and a carrier comprising5 wt. % of a purified phospholipid (Lipoid LLC), 46.5 wt. % of apurified triglyceride (TG) (Spectrum Chemical Manufacturing Corporation)and 48.5 wt. % of oleic acid (Spectrum Chemical ManufacturingCorporation) designed NAP Formula D.

NAP Formula D was prepared by admixing 50 wt. % NAPprofen (NAP) into acarrier comprising 23.25 wt. % triglycerides derived from Soy bean oil,24.25 wt. % oleic acid and 2.5 wt. % of purified phosphatidylcholine ata temperature of about 40° C. for about 30 minutes as described above.

Partitioning Study of NAP Vs. NAP Formulas A-D

In this study, pure naproxen (NAP) partitioning between cyclohexane andwater versus NAP partitioning between cyclohexane and water in NAPFormulas A-D was investigated at pH 1 and at pH 7 simulating gastricfluids and duodenum fluids. The study was conducted by adding eitherNAP, NAP Formulas A-D into a cyclohexane/water partitioning system andmeasuring the differential partitioning of NAP between the two phase asthe value Log P.

Referring now to FIG. 17, it is clear that NAP partitions differently atpH 1 versus pH7. NAP has a Log P of 0.65 at pH 1 and a Log P of −2.06 atpH 7. The partitioning of NAP in NAP Formulas A-D between cyclohexaneand water at pH 1 as measured by Log P is higher than the Log P value ofNAP at pH 1. The partitioning of NAP in NAP Formulas A-D betweencyclohexane and water at pH 7 as measured by Log P is also higher thanthe Log P value for NAP at pH 7. Thus, while NAP shows a substantial pHdependent release, the NAP Formulas A-D also showed the pH dependentrelease behavior.

Indomethacin

Preparation of INDO Formulas A-D

INDO Formula A

This example illustrates the preparation by admixing of a compositionincluding a 1:1 weight ratio of indomethacin (INDO) and a carriercomprising about 40 wt. % of a purified phosphatidylcholine (PC) and apure triglyceride (TG) designed INDO Formula A.

INDO Formula A was prepared by admixing 50 wt. % INDO into a carrierincluding 30 wt. % triglycerides derived from Soy bean oil from SpectrumOL103, lot 1AI0411 and 20 wt. % of purified phosphatidylcholine fromLipoid S100, Charge 790569-10/0 at a temperature of about 40° C. forabout 30 minutes as descried above.

INDO Formula B

This example illustrates the preparation by admixing of a compositionincluding a 1:1 weight ratio of indomethacin (INDO) and a carriercomprising the lecithin oil Phosal 35SB (PS35SB) designed INDO FormulaB.

INDO Formula B was prepared by admixing 50 wt. % INDO into a carriercomprising 50 wt. % PS35SB at a temperature of about 40° C. for about 30minutes as described above.

INDO Formula C

This example illustrates the preparation by admixing of a compositionsincluding a 1:1 weight ratio of indomethacin (INDO) and a carriercomprising 42 wt. % of a purified phospholipid, 28 wt. % of a purifiedtriglyceride (TG) from Spectrum OL103, lot 1 AI0411 and 30 wt. % ofoleic acid designed INDO Formula C.

INDO Formula C was prepared by admixing 50 wt. % INDO into a carriercomprising 14 wt. % triglycerides derived from Soy bean oil, 15 wt. %oleic acid and 21 wt. % of purified phosphatidylcholine at a temperatureof about 40° C. for about 30 minutes as described above.

INDO Formula D

This example illustrates the preparation by admixing of a compositionsincluding a 1:1 weight ratio of indomethacin (INDO) and a carriercomprising 5 wt. % of a purified phospholipid, 46.5 wt. % of a purifiedtriglyceride (TG) and 48.5 wt. % of oleic acid designed INDO Formula D.

INDO Formula D was prepared by admixing 50 wt. % INDO into a carriercomprising 23.25 wt. % triglycerides derived from Soy bean oil, 24.25wt. % oleic acid and 2.5 wt. % of purified phosphatidylcholine at atemperature of about 40° C. for about 30 minutes as described above.

Partitioning Study of INDO Vs. INDO Formulas A-D

In this study, pure indomethacin (INDO) partitioning between cyclohexaneand water versus INDO partitioning between cyclohexane and water in INDOFormulas A-D was investigated at pH 1 and at pH 7 simulating gastricfluids and duodenum fluids. The study was conducted by adding eitherINDO, INDO Formulas A-D into a cyclohexane/water partitioning system andmeasuring the differential partitioning of INDO between the two phase asthe value Log P.

Referring now to FIG. 18, it is clear that INDO partitions differentlyat pH 1 versus pH7. INDO has a Log P of 1.05 at pH 1 and a Log P of−1.81 at pH 7. The partitioning of INDO in INDO Formulas A-D betweencyclohexane and water at pH 1 as measured by Log P is higher than theLog P value of NAP at pH 1. The partitioning of INDO in INDO FormulasA-D between cyclohexane and water at pH 7 as measured by Log P is alsohigher than the Log P value for INDO at pH 7. Thus, while INDO shows asubstantial pH dependent release, the INDO Formulas A-D also showed thepH dependent release behavior.

Mefenamic Acid

Preparation of MFA Formulas A-D

MFA Formula A

This example illustrates the preparation by admixing of a compositionincluding a 1:1 weight ratio of mefenamic acid (MFA) and a carriercomprising about 40 wt. % of a purified phosphatidylcholine (PC) and apure triglyceride (TG) designed MFA Formula A.

MFA Formula A was prepared by admixing 50 wt. % MFA into a carrierincluding 30 wt. % triglycerides derived from Soy bean oil from SpectrumOL103, lot 1 AI0411 and 20 wt. % of purified phosphatidylcholine fromLipoid S100, Charge 790569-10/019 at a temperature of about 40° C. forabout 30 minutes as descried above.

MFA Formula B

This example illustrates the preparation by admixing of a compositionincluding a 1:1 weight ratio of mefenamic acid (MFA) and a carriercomprising the lecithin oil Phosal 35SB (PS35SB) designed MFA Formula B.

MFA Formula B was prepared by admixing 50 wt. % MFA into a carriercomprising 50 wt. % PS35SB at a temperature of about 40° C. for about 30minutes as described above.

MFA Formula C

This example illustrates the preparation by admixing of a compositionsincluding a 1:1 weight ratio of mefenamic acid (MFA) and a carriercomprising 42 wt. % of a purified phospholipid, 28 wt. % of a purifiedtriglyceride (TG) and 30 wt. % of oleic acid designed MFA Formula C.

MFA Formula C was prepared by admixing 50 wt. % MFA into a carriercomprising 14 wt. % triglycerides derived from Soy bean oil fromSpectrum OL103, lot 1A10411, 15 wt. % oleic acid and 21 wt. % ofpurified phosphatidylcholine at a temperature of about 40° C. for about30 minutes as described above.

MFA Formula D

This example illustrates the preparation by admixing of a compositionsincluding a 1:1 weight ratio of mefenamic acid (MFA) and a carriercomprising 5 wt. % of a purified phospholipid, 46.5 wt. % of a purifiedtriglyceride (TG) and 48.5 wt. % of oleic acid designed MFA Formula D.

MFA Formula D was prepared by admixing 50 wt. % MFA into a carriercomprising 23.25 wt. % triglycerides derived from Soy bean oil, 24.25wt. % oleic acid and 5 wt. % of purified phosphatidylcholine at atemperature of about 40° C. for about 30 minutes as described above.

Partitioning Study of MFA Vs. MFA Formulas A-D

In this study, pure mefenamic acid (MFA) partitioning betweencyclohexane and water versus MFA partitioning between cyclohexane andwater in MFA Formulas A-D was investigated at pH 1 and at pH 7simulating gastric fluids and duodenum fluids. The study was conductedby adding either MFA, MFA Formulas A-D into a cyclohexane/waterpartitioning system and measuring the differential partitioning of MFAbetween the two phase as the value Log P.

Referring now to FIG. 19, it is clear that MFA partitions differently atpH 1 versus pH7. MFA has a Log P of 0.00 at pH 1 and a Log P of 0.47 atpH 7. The partitioning of MFA in MFA Formulas A-D between cyclohexaneand water at pH 1 as measured by Log P is significantly more positivethan the Log P value of MFA at pH 1, showing little difference betweenthe oil based carriers. The partitioning of MFA in MFA Formulas A-Dbetween cyclohexane and water at pH 7 as measured by Log P only showed aslightly higher value than the Log P value for MFA at pH 7, except forMFA Formula A, which shows a slightly lower value than the Log P valuefor MFA at pH 7. Thus, while MFA shows a substantial pH dependentrelease, the MFA Formulas A-D also showed the pH dependent releasebehavior.

Summary of Weak Acid Partitioning Data

From the data presented above for aspirin, salicylic acid, naproxen,indomethacin, and mefenamic acid, it is clear the carriers including asufficient amount of free fatty acid release these weak acids in a pHdependent manner so that the weak acid biologically active agents may betargeted to higher pH values as the agents leave the low pH environmentof the stomach. As this targeted release of the active agents from thelipid matrix appears to be due to ionization state of the free fattyacid in the carrier relative to pH and other physiological milieu ofselected regions of the GI tract. Thus, targeted release of anybiologically active agent should be possible, and particularly usefulfor active ingredients that are a) injurious to the upper GI tract(stomach and duodenum), b) acid labile active, c) insoluble/impermeablecompounds GI fluids and d) susceptible to first pass metabolism.

CLOSING

All references cited herein are incorporated by reference. Although theinvention has been disclosed with reference to its preferredembodiments, from reading this description those of skill in the art mayappreciate changes and modification that may be made which do not departfrom the scope and spirit of the invention as described above andclaimed hereafter.

1-23. (canceled)
 24. A method of targeting release of a biologicallyactive agent to the small intestine of a subject, comprising orallyadministering to the subject an ingestible pharmaceutical composition,wherein: (i) the pharmaceutical composition comprises a suspension of acrystalline solid, biologically active agent in a non-aqueous liquidcarrier, (ii) the weight ratio of the active agent to the non-aqueousliquid carrier is between about 50:1 and about 1:10, (iii) thepharmaceutical composition is a solid-in-oil suspension that issubstantially free of water, and (iv) the non-aqueous carrier is an oil,wherein: (a) the carrier comprises at least 10 wt % of freemonocarboxylic acid having at least 8 carbons, wherein themonocarboxylic acid is liquid at room temperature; (b) the carriercomprises from about 0.0001 wt. % to about 5 wt. % of zwitterionicphospholipids; and (c) the pharmaceutical composition releases a lesseramount of active agent at a pH of <3 than at pH>3, wherein thecomposition is formulated in the absence of a solvent.
 25. The method ofclaim 24, wherein less than 20% of the biologically active agent isreleased from the non-aqueous liquid carrier at pH<3 and greater than50% of the biologically active agent is released from the non-aqueousliquid carrier at pH>3.
 26. The method of claim 24, wherein thenon-aqueous liquid carrier releases a lesser amount of biologicallyactive agent at pH<5 than at pH>5.
 27. The method of claim 24, whereinthe biologically active agent comprises at least one agent selected fromthe group consisting of an acid-labile pharmaceutical agent, ananti-depressant, an anti-diabetic agent, an anti-epileptic agent, ananti-fungal agent, an anti-malarial agent, an anti-muscarinic agent, ananti-neoplastic agent, an immunosuppressant, an anti-protozoal agent, ananti-tussive, a neuroleptics, a beta-blocker, a cardiac inotropic agent,a corticosteroid, an anti-parkinsonian agent, a gastrointestinal agent,histamine, a histamine receptor antagonist, a keratolytic, a lipidregulating agent, a muscle relaxant, a nitrate, an anti-anginal agent, anutritional agent, an opioid analgesic, a sex hormone, a stimulant, anutraceutical, a peptide, a protein, a therapeutic protein, anucleoside, a nucleotide, DNA, RNA, a glycosaminoglycan, an acid-labiledrug,(+)-N{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-Nhydroxyurea,amylase, aureomycin, bacitracin, beta carotene, cephalosporins,chloromycetin, cimetidine, cisapride, cladribine, clorazepate,deramciclane, didanosine, digitalis glycosides, dihydrostreptomycin,erythromycin, etoposide, famotidine, a hormone, estrogen, insulin,adrenalin, heparin, lipase, milameline, novobiocin, pancreatin,penicillin salts, polymyxin, pravastatin, progabide, protease,quinapril, quinoxaline-2-carboxylic acid,[4-(R)carbamoyl-1-(S-3-fluorobenzyl-2-(S),7-dihydroxy-7-methyloctyl]amide-,quinoxaline-2-carboxylicacid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide,ranitidine, streptomycin, subtilin, sulphanilamide, a proton pumpinhibitors, esomeprazole, lansoprazole, minoprazole, omeprazole,pantoprazole and rabeprazole.
 28. The method of claim 27, wherein thebiologically active agent is an acid-labile drug.
 29. The method ofclaim 28, wherein the acid-labile drug is selected from the groupconsisting of heparin, insulin, erythropoietin, pancreatin,lansoprazole, omeprazole, pantoprazole, rabeprazole, penicillin salts,benzathine penicillin, polymyxin, sulphanilamide, and erythromycin. 30.The method of claim 24, wherein the non-aqueous liquid carrier furthercomprises at least one component selected from the group consisting ofan adjuvant, a mixture of adjuvants, an antioxidant, a mixture ofantioxidants, a viscomodulator, a mixture of viscomodulators, and apermeability-improving agent.
 31. A method of targeting release of abiologically active agent to the small intestine of a subject,comprising orally administering to the subject an ingestiblepharmaceutical composition, wherein: (i) the pharmaceutical compositionis made by admixing a solid biologically active agent into a non-aqueousliquid carrier, (ii) the composition is formulated for oraladministration, (iii) the weight ratio of the active agent to thenon-aqueous liquid carrier is between about 50:1 and about 1:10, and(iv) the non-aqueous liquid carrier is an oil, wherein: (a) the carriercomprises at least about 10 wt % of a free monocarboxylic acid having atleast 8 carbons, wherein the monocarboxylic acid is liquid at roomtemperature; (b) the carrier is substantially free of water; (c) thecarrier comprises from about 0.0001 wt. % to about 5 wt. % ofzwitterionic phospholipids; and (d) the pharmaceutical compositionreleases a lesser amount of active agent at a pH of <3 than at pH>3,wherein the composition is formulated in the absence of a solvent. 32.The method of claim 31, wherein the solid biologically active agentcomprises crystals of the biologically active agent.
 33. The method ofclaim 31, wherein: (a) less than about 20% of the biologically activeagent is released from the non-aqueous liquid carrier at pH<3; and (b)greater than about 50% of the biologically active agent is released fromthe non-aqueous liquid carrier at pH>3.
 34. The method of claim 31,wherein the biologically active agent comprises at least one agentselected from the group consisting of an acid-labile pharmaceuticalagent, an anti-depressant, an anti-diabetic agent, an anti-epilepticagent, an anti-fungal agent, an anti-malarial agent, an anti-muscarinicagent, an anti-neoplastic agent, an immunosuppressant, an anti-protozoalagent, an anti-tussive, a neuroleptics, a betablocker, a cardiacinotropic agent, a corticosteroid, an anti-parkinsonian agent, agastrointestinal agent, histamine, a histamine receptor antagonist, akeratolytic, a lipid regulating agent, a muscle relaxant, a nitrate, ananti-anginal agent, a nutritional agent, an opioid analgesic, a sexhormone, a stimulant, a nutraceutical, a peptide, a protein, atherapeutic protein, a nucleoside, a nucleotide, DNA, RNA, aglycosaminoglycan, an acid-labile drug, (+)-N{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea,amylase, aureomycin, bacitracin, beta carotene, cephalosporins,chloromycetin, cimetidine, cisapride, cladribine, clorazepate,deramciclane, didanosine, digitalis glycosides, dihydrostreptomycin,erythromycin, etoposide, famotidine, a hormone, estrogen, insulin,adrenalin, heparin, lipase, milameline, novobiocin, pancreatin,penicillin salts, polymyxin, pravastatin, progabide, protease,quinapril, quinoxaline-2-carboxylic acid,[4-(R)carbamoyl-1-(S-3-fluorobenzyl-2-(S),7-dihydroxy-7-methyloctyl]amide-, quinoxaline-2-carboxylicacid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide,ranitidine, streptomycin, subtilin, sulphanilamide, a proton pumpinhibitors, esomeprazole, lansoprazole, minoprazole, omeprazole,pantoprazole and rabeprazole.
 35. The method of claim 34, wherein thebiologically active agent is an acid-labile drug.
 36. The method ofclaim 35, wherein the acid-labile drug is selected from the groupconsisting of heparin, insulin, erythropoietin, pancreatin,lansoprazole, omeprazole, pantoprazole, rabeprazole, penicillin salts,benzathine penicillin, polymyxin, sulphanilamide, and erythromycin. 37.The method of claim 31, wherein the non-aqueous liquid carrier furthercomprises at least one component selected from the group consisting ofan adjuvant, a mixture of adjuvants, an antioxidant, a mixture ofantioxidants, a viscomodulator, a mixture of viscomodulators, and apermeability-improving agent.
 38. The method of claim 24, wherein themonocarboxylic acid is a medium chain free fatty acid or avery-long-chain free fatty acid.
 39. The method of claim 31, wherein themonocarboxylic acid is a medium chain free fatty acid or avery-long-chain free fatty acid.
 40. The method of claim 24, wherein themonocarboxylic acid is unsaturated.
 41. The method of claim 31, whereinthe monocarboxylic acid is unsaturated.
 42. The method of claim 24,wherein the weight ratio of active agent to carrier is between about25:1 and about 1:5.
 43. The method of claim 31, wherein the weight ratioof active agent to carrier is between about 25:1 and about 1:5.
 44. Themethod of claim 24, wherein the weight ratio of active agent to carrieris between about 25:1 and about 1:1.
 45. The method of claim 31, whereinthe weight ratio of active agent to carrier is between about 25:1 andabout 1:1.
 46. The method of claim 24, wherein the non-aqueous liquidcarrier is substantially free of fatty acid salt.
 47. The method ofclaim 31, wherein the non-aqueous liquid carrier is substantially freeof fatty acid salt.